研究者詳細 - 冨樫　庸介

論文 - 冨樫　庸介

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Close Spatial Interactions between Cancer Cells and Cancer-Associated Fibroblasts Suppress Antitumor Immunity. 査読国際誌

Yuto Naoi, Yumi Inukai, Tomoka Izumikawa, Joji Nagasaki, Takamasa Ishino, Youki Ueda, Yin Min Thu, Miho Fujiwara, Takahiro Baba, Go Makimoto, Ken Suzawa, Kazuhiro Okada, Ken-Ichi Yamamoto, Masakiyo Sakaguchi, Shuta Tomida, Yoshinobu Maeda, Shinichi Toyooka, Mizuo Ando, Yosuke Togashi

Cancer immunology research 2025年7月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Cancer-associated fibroblasts (CAFs) play immunosuppressive roles in the tumor microenvironment (TME). Specifically, they reportedly act as physical barriers preventing immune cell infiltration. However, the spatial relationships between CAFs and cancer cells in antitumor immunity remain unknown. In this study, we established three-dimensional (3D) constructs, in which the spatial relationships were controlled using a 3D bioprinter. Using these models, we found that the mixed distribution of fibroblasts (FBs) and cancer cells suppressed the antitumor immunity more than the surrounding distribution of FBs as physical barriers. The 3D construct with mixed distribution promoted transforming growth factor (TGF)-β and periostin (encoded by Postn gene) crosstalk, resulting in immunosuppression. Postn-knockdown in FBs decreased the TGF-β production in the mixed 3D construct and activated antitumor immunity both in vitro and in vivo. Clinically, patients with head and neck cancer or lung cancer showing mixed distribution of α-smooth muscle actin+ myofibroblast-like CAFs exhibited worse prognosis after programmed death protein-1 blockade therapies, and lower CD8+ T cell infiltration than those that had CAFs surrounding cancer cells. Overall, our findings suggest that the close interactions of CAFs and cancer cells facilitate immunosuppression, rather than the physical barriers created by CAFs, highlighting their potential as biomarkers and therapeutic targets for cancer immunotherapies based on spatial relationships. Furthermore, this study highlights the beneficial applications of 3D bioprinters.

DOI： 10.1158/2326-6066.CIR-24-1144

A Prompt Diagnosis of Ascites and Dramatic Effect of Alectinib for Advanced Lung Adenocarcinoma Harboring EML4-ALK Fusion: A Case Report.

Takahiro Baba, Hirofumi Inoue, Hiromi Matsuoka, Mio Kyakuno, Yusuke Yoshinaga, Tetsuya Takeguchi, Miho Fujiwara, Kotaro Yamada, Eri Nakamura, Ayako Morita, Naofumi Hara, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Eiki Ichihara, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Yosuke Togashi, Go Makimoto

Internal medicine (Tokyo, Japan) 2025年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 75-year-old never-smoker woman presented with dyspnea and loss of appetite. A mass was identified in the left upper lobe of the lung, and the patient was referred to our hospital. Despite the diagnosis of lung adenocarcinoma via bronchoscopy, ALK immunostaining was negative. Rapid weight gain and abdominal distension caused by ascites prompted fluid testing using the AmoyDx Pan Lung Cancer PCR Panel. EML4-ALK fusion was confirmed, and alectinib therapy was initiated immediately. The tumor size had decreased significantly, and the patient was discharged on day 34. This case highlights the necessity of multiplex genetic testing even when ALK immunostaining is negative.

DOI： 10.2169/internalmedicine.5397-25

High Antigenicity for Treg Cells Confers Resistance to PD-1 Blockade Therapy via High PD-1 Expression in Treg Cells. 査読国際誌

Hiroaki Matsuura, Takamasa Ishino, Toshifumi Ninomiya, Kiichiro Ninomiya, Kota Tachibana, Akiko Honobe-Tabuchi, Yoshinori Muto, Takashi Inozume, Youki Ueda, Kadoaki Ohashi, Yoshinobu Maeda, Joji Nagasaki, Yosuke Togashi

Cancer science 116 ( 5 ) 1214 - 1226 2025年5月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Regulatory T (Treg) cells have an immunosuppressive function, and programmed death-1 (PD-1)-expressing Treg cells reportedly induce resistance to PD-1 blockade therapies through their reactivation. However, the effects of antigenicity on PD-1 expression in Treg cells and the resistance to PD-1 blockade therapy remain unclear. Here, we show that Treg cells gain high PD-1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for Treg cells were resistant to PD-1 blockade in vivo due to PD-1+ Treg-cell infiltration. Because such PD-1+ Treg cells have high cytotoxic T lymphocyte antigen (CTLA)-4 expression, resistance could be overcome by combination with an anti-CTLA-4 monoclonal antibody (mAb). Patients who responded to combination therapy with anti-PD-1 and anti-CTLA-4 mAbs sequentially after primary resistance to PD-1 blockade monotherapy showed high Treg cell infiltration. We propose that the high antigenicity of Treg cells confers resistance to PD-1 blockade therapy via high PD-1 expression in Treg cells, which can be overcome by combination therapy with an anti-CTLA-4 mAb.

DOI： 10.1111/cas.70029

Efficacy of amivantamab, a bi-specific antibody targeting EGFR and MET, in ALK-rearranged non-small-cell lung cancer cell lines. 査読国際誌

Tatsuya Nishi, Ayako Morita, Naofumi Hara, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yosuke Togashi, Yoshinobu Maeda, Eiki Ichihara

Lung cancer (Amsterdam, Netherlands) 201 108415 - 108415 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective in treating ALK-rearranged non-small-cell lung cancer (NSCLC). However, at least 40% of patients develop acquired resistance during treatment. Adaptive or acquired resistance to ALK TKIs could be mediated through epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling. Sixteen percent of acquired resistance cases are linked to bypass signaling. METHODS: In this study, we evaluated the effects of amivantamab, a bi-specific antibody targeting both EGFR and MET, on ALK-rearranged NSCLC cells. We investigated the effect of amivantamab on the ALK-rearranged NSCLC cell lines H3122, ABC-19, and ABC-11. RESULTS: Combining alectinib with amivantamab resulted in greater inhibition of cell growth inhibition in H3122 and ABC-19 cells compared to alectinib alone, but not in ABC-11 cells. EGFR TKI erlotinib showed similar efficacy in H3122 and ABC-19 cells, whereas MET TKI tepotinib was ineffective in both, suggesting that the efficacy of amivantamab is through EGFR inhibition. Unlike H3122 and ABC-19 cells, ABC-11 cells were resistant to EGFR/MET signaling inhibition. Interestingly, amivantamab enhanced alectinib efficacy against ABC-11 cells in the presence of peripheral blood mononuclear cells (PBMCs), despite showing no effect alone without PBMCs, suggesting action through non-signal inhibitory mechanisms. Finally, we treated alectinib-resistant cellswith alectinib, with or without amivantamab, and found that amivantamab restored the sensitivity of these cells to alectinib. CONCLUSION: The bi-specific antibody amivantamab, which targets EGFR and MET, enhanced the efficacy of alectinib through both signal and non-signal inhibitory mechanisms in ALK-rearranged NSCLC cells.

DOI： 10.1016/j.lungcan.2025.108415

Publisher Correction: Immune evasion through mitochondrial transfer in the tumour microenvironment. 国際誌

Hideki Ikeda, Katsushige Kawase, Tatsuya Nishi, Tomofumi Watanabe, Keizo Takenaga, Takashi Inozume, Takamasa Ishino, Sho Aki, Jason Lin, Shusuke Kawashima, Joji Nagasaki, Youki Ueda, Shinichiro Suzuki, Hideki Makinoshima, Makiko Itami, Yuki Nakamura, Yasutoshi Tatsumi, Yusuke Suenaga, Takao Morinaga, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Yukiko Kiniwa, Eiki Ichihara, Hidetoshi Hayashi, Jun-Ichiro Ikeda, Toyoyuki Hanazawa, Shinichi Toyooka, Hiroyuki Mano, Takuji Suzuki, Tsuyoshi Osawa, Masahito Kawazu, Yosuke Togashi

Nature 639 ( 8053 ) E5 2025年3月

Immune evasion through mitochondrial transfer in the tumour microenvironment. 査読国際誌

Hideki Ikeda, Katsushige Kawase, Tatsuya Nishi, Tomofumi Watanabe, Keizo Takenaga, Takashi Inozume, Takamasa Ishino, Sho Aki, Jason Lin, Shusuke Kawashima, Joji Nagasaki, Youki Ueda, Shinichiro Suzuki, Hideki Makinoshima, Makiko Itami, Yuki Nakamura, Yasutoshi Tatsumi, Yusuke Suenaga, Takao Morinaga, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Yukiko Kiniwa, Eiki Ichihara, Hidetoshi Hayashi, Jun-Ichiro Ikeda, Toyoyuki Hanazawa, Shinichi Toyooka, Hiroyuki Mano, Takuji Suzuki, Tsuyoshi Osawa, Masahito Kawazu, Yosuke Togashi

Nature 638 ( 8049 ) 225 - 236 2025年1月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2-4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.

DOI： 10.1038/s41586-024-08439-0

Myeloid Cells Induce Infiltration and Activation of B Cells and CD4+ T Follicular Helper Cells to Sensitize Brain Metastases to Combination Immunotherapy. 査読国際誌

Toshifumi Ninomiya, Naoya Kemmotsu, Fumiaki Mukohara, Masaki Magari, Ai Miyamoto, Youki Ueda, Takamasa Ishino, Joji Nagasaki, Tomohiro Fujiwara, Hidetaka Yamamoto, Hidetoshi Hayashi, Kota Tachibana, Joji Ishida, Yoshihiro Otani, Shota Tanaka, Shinichi Toyooka, Isamu Okamoto, Yosuke Togashi

Cancer research 2025年1月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Brain metastasis (BM) is a poor prognostic factor in cancer patients. Despite showing efficacy in many extracranial tumors, immunotherapy with anti-PD-1 monoclonal antibody (mAb) or anti-CTLA-4 mAb appears to be less effective against intracranial tumors. Promisingly, recent clinical studies have reported that combination therapy with anti-PD-1 and anti-CTLA-4 mAbs has a potent antitumor effect on BM, highlighting the need to elucidate the detailed mechanisms controlling the intracranial tumor microenvironment (TME) to develop effective immunotherapeutic strategies. Here, we analyzed the tumor-infiltrating lymphocytes in murine models of BM that responded to anti-CTLA-4 mAb to anti-PD-1 mAb. Activated CD4+ T follicular helper (TFH) cells with high CTLA-4 expression characteristically infiltrated the intracranial TME, which were activated by the combination anti-CTLA-4 and anti-PD-1 treatment. Loss of TFH cells suppressed the additive effect of CTLA-4 blockade on anti-PD-1 mAb. B cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) produced by abundant myeloid cells, particularly CD80hiCD206lo pro-inflammatory M1-like macrophages, in the intracranial TME, induced B cell and TFH cell infiltration and activation. Furthermore, the intracranial TME of patients with non-small cell lung cancer featured TFH and B cell infiltration as tertiary lymphoid structures. Together, these findings provide insights into the immune cell crosstalk in the intracranial TME that facilitates an additive anti-tumor effect of CTLA-4 blockade with anti-PD-1 treatment, supporting the potential of a combination immunotherapeutic strategy for BM.

DOI： 10.1158/0008-5472.CAN-24-2274

The tumor immune microenvironment and therapeutic efficacy of trastuzumab deruxtecan in gastric cancer. 査読国際誌

Shigehiro Koganemaru, Shohei Koyama, Fumitaka Suto, Makito Koga, Koichiro Inaki, Yusuke Kuwahara, Takeo Arita, Tsuyoshi Hirata, Hiroki Goto, Naoya Wada, Maki Kobayashi, Tomoko Shibutani, Tatsuya Okabayashi, Kenji Nakamaru, Akihito Kawazoe, Yosuke Togashi, Hiroyoshi Nishikawa, Kohei Shitara

Cancer research communications 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody-drug conjugate with a topoisomerase I inhibitor connected by a cleavable linker, has been approved for patients with HER2-positive gastric or gastroesophageal junction tumors. This biomarker study assessed HER2 expression and immune cell infiltration in relation to the therapeutic response to T-DXd. This retrospective analysis included samples from patients treated with T-DXd in three clinical trials. We performed RNA sequencing and multiplex immunohistochemistry on archival tumor samples obtained at baseline, during treatment, and after treatment. Flow cytometry was performed on tumor infiltrating immune cells freshly isolated from tumor tissues. Samples from 28 patients were included in this study. ERBB2 mRNA levels and CD20+ cell infiltration in tumors were significantly higher at baseline in responders than in nonresponders. Patients were classified into three biological groups based on their baseline tumor/stroma-infiltrating immune cell densities. Two groups reported similar response rates, but a trend was observed toward a shorter progression-free-survival in the group with more immunosuppressive regulatory T cells and programmed death-ligand 1 (PD-L1) expression at baseline. T-DXd treatment tended to increase the levels of tumor-infiltrating CD8+ T cells and PD1+CD8+ T cells, particularly in responders. Gene expression signatures of CTL and helper T cells increased during treatment, whereas signatures related to hypoxia, MYC targets, collagen formation, and interleukin-10 were downregulated. Our data suggest that HER2 expression levels and baseline tumor microenvironment (TME) characteristics correlate with T-DXd efficacy. Furthermore, this treatment may modulate TME immune profiles. Further validation using a larger sample size is warranted.

DOI： 10.1158/2767-9764.CRC-24-0302

The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment. 査読国際誌

Ayaka Tsuge, Sho Watanabe, Akihito Kawazoe, Yosuke Togashi, Kota Itahashi, Mari Masuda, Atsuo Sai, Shogo Takei, Hiromi Muraoka, Shuichi Ohkubo, Daisuke Sugiyama, Yue Yan, Shota Fukuoka, Toshihiko Doi, Kohei Shitara, Shohei Koyama, Hiroyoshi Nishikawa

Cancer immunology research 13 ( 2 ) 273 - 285 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to programmed death (PD)-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment (TME), has been intensively studied. Inhibition of heat shock protein 90 (HSP90), a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects. Here, we show that the number of Treg cells are selectively reduced by the HSP90 inhibitor pimitespib in animal models and patients with gastric cancer in a clinical trial (EPOC1704). Pimitespib reduced the highly immunosuppressive human FOXP3high effector Treg cells by inhibiting their proliferation and decreasing their expression of effector molecules, which improved the priming and activation of antigen-specific CD8+ T cells. Mechanistic studies revealed that pimitespib selectively degraded STAT5, a key transducer of the IL-2 signaling pathway, which is essential for Treg cell development and maintenance, and consequently compromised FOXP3 expression, leading to selective impairment of immunosuppression in the TME by Treg cells. Thus, pimitespib treatment combined with PD-1 blockade exhibited a far stronger antitumor effect than either treatment alone in animal models. Through these data, we propose that HSP90 inhibition is a promising therapeutic option for Treg cell-targeted cancer immunotherapy.

DOI： 10.1158/2326-6066.CIR-24-0713

Author Correction: Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling. 国際誌

Takahiro Nakajima, Toshio Kanno, Yuki Ueda, Keisuke Miyako, Takeru Endo, Souta Yoshida, Satoru Yokoyama, Hikari K Asou, Kazuko Yamada, Kazutaka Ikeda, Yosuke Togashi, Yusuke Endo

Cellular & molecular immunology 21 ( 11 ) 1350 - 1350 2024年11月

Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity. 査読国際誌

Fumiaki Mukohara, Kazuma Iwata, Takamasa Ishino, Takashi Inozume, Joji Nagasaki, Youki Ueda, Ken Suzawa, Toshihide Ueno, Hideki Ikeda, Katsushige Kawase, Yuka Saeki, Shusuke Kawashima, Kazuo Yamashita, Yu Kawahara, Yasuhiro Nakamura, Akiko Honobe-Tabuchi, Hiroko Watanabe, Hiromichi Dansako, Tatsuyoshi Kawamura, Yutaka Suzuki, Hiroaki Honda, Hiroyuki Mano, Shinichi Toyooka, Masahito Kawazu, Yosuke Togashi

Proceedings of the National Academy of Sciences of the United States of America 121 ( 35 ) e2320189121 2024年8月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Immune checkpoint inhibitors (ICIs) exert clinical efficacy against various types of cancers by reinvigorating exhausted CD8+ T cells that can expand and directly attack cancer cells (cancer-specific T cells) among tumor-infiltrating lymphocytes (TILs). Although some reports have identified somatic mutations in TILs, their effect on antitumor immunity remains unclear. In this study, we successfully established 18 cancer-specific T cell clones, which have an exhaustion phenotype, from the TILs of four patients with melanoma. We conducted whole-genome sequencing for these T cell clones and identified various somatic mutations in them with high clonality. Among the somatic mutations, an SH2D2A loss-of-function frameshift mutation and TNFAIP3 deletion could activate T cell effector functions in vitro. Furthermore, we generated CD8+ T cell-specific Tnfaip3 knockout mice and showed that Tnfaip3 function loss in CD8+ T cell increased antitumor immunity, leading to remarkable response to PD-1 blockade in vivo. In addition, we analyzed bulk CD3+ T cells from TILs in additional 12 patients and identified an SH2D2A mutation in one patient through amplicon sequencing. These findings suggest that somatic mutations in TILs can affect antitumor immunity and suggest unique biomarkers and therapeutic targets.

DOI： 10.1073/pnas.2320189121

Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling. 査読国際誌

Takahiro Nakajima, Toshio Kanno, Yuki Ueda, Keisuke Miyako, Takeru Endo, Souta Yoshida, Satoru Yokoyama, Hikari K Asou, Kazuko Yamada, Kazutaka Ikeda, Yosuke Togashi, Yusuke Endo

Cellular & molecular immunology 21 ( 11 ) 1350 - 1350 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

T helper 9 (Th9) cells are interleukin 9 (IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation. Th9 cells differentiate from naïve CD4+ T cells in the presence of IL-4 and transforming growth factor-beta (TGF-β); however, our understanding of the molecular basis of their differentiation remains incomplete. Previously, we reported that the differentiation of another subset of TGF-β-driven T helper cells, Th17 cells, is highly dependent on de novo lipid biosynthesis. On the basis of these findings, we hypothesized that lipid metabolism may also be important for Th9 cell differentiation. We therefore investigated the differentiation and function of mouse and human Th9 cells in vitro under conditions of pharmacologically or genetically induced deficiency of the intracellular fatty acid content and in vivo in mice genetically deficient in acetyl-CoA carboxylase 1 (ACC1), an important enzyme for fatty acid biosynthesis. Both the inhibition of de novo fatty acid biosynthesis and the deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells. Mechanistic studies revealed that the increase in Th9 cell differentiation was mediated by the retinoic acid receptor and the TGF-β-SMAD signaling pathways. Upon adoptive transfer, ACC1-inhibited Th9 cells suppressed tumor growth in murine models of melanoma and adenocarcinoma. Together, our findings highlight a novel role of fatty acid metabolism in controlling the differentiation and in vivo functions of Th9 cells.

DOI： 10.1038/s41423-024-01209-y

Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B-NIT). 査読国際誌

Takuya Fujimoto, Osamu Yamasaki, Noriyuki Kanehira, Hirokazu Matsushita, Yoshinori Sakurai, Naoya Kenmotsu, Ryo Mizuta, Natsuko Kondo, Takushi Takata, Mizuki Kitamatsu, Kazuyo Igawa, Atsushi Fujimura, Yoshihiro Otani, Makoto Shirakawa, Kunitoshi Shigeyasu, Fuminori Teraishi, Yosuke Togashi, Minoru Suzuki, Toshiyoshi Fujiwara, Hiroyuki Michiue

Cancer science 115 ( 10 ) 3231 - 3247 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44+ effector memory T cells and CD69+ early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers.

DOI： 10.1111/cas.16298

Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model. 査読国際誌

Kazuhiro Okumura, Takao Morinaga, Megumi Saito, Yurika Tokunaga, Keisuke Otoyama, Sora Tanaka, Eriko Isogai, Masahito Kawazu, Yosuke Togashi, Yoshinori Hasegawa, Yuichi Wakabayashi

Cancer science 115 ( 8 ) 2839 - 2845 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

By taking advantage of forward genetic analysis in mice, we have demonstrated that Pak1 plays a crucial role during DMBA/TPA skin carcinogenesis. Although Pak1 has been considered to promote cancer development, its overall function remains poorly understood. To clarify the functional significance of Pak1 in detail, we sought to evaluate the possible effect of an allosteric inhibitor against PAK1 (NVS-PAK1-1) on a syngeneic mouse model. To this end, we established two cell lines, 9AS1 and 19AS1, derived from DMBA/TPA-induced squamous cell carcinoma (SCC) that engrafted in FVB mice. Based on our present results, NVS-PAK1-1 treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo. RNA-sequencing analysis on the engrafted tumors indicates that NVS-PAK1-1 markedly potentiates the epidermal cell differentiation and enhances the immune response in the engrafted tumors. Consistent with these observations, we found an expansion of Pan-keratin-positive regions and potentially elevated infiltration of CD8-positive immune cells in NVS-PAK1-1-treated tumors as examined by immunohistochemical analyses. Together, our present findings strongly suggest that PAK1 is tightly linked to the development of SCC, and that its inhibition is a promising therapeutic strategy against SCC.

DOI： 10.1111/cas.16246

CD106 in tumor-specific exhausted CD8+ T cells mediates immunosuppression by inhibiting TCR signaling. 査読国際誌

Yuto Naoi, Takao Morinaga, Joji Nagasaki, Ryo Ariyasu, Youki Ueda, Kazuo Yamashita, Wenhao Zhou, Shusuke Kawashima, Katsushige Kawase, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yu Kawahara, Yasuhiro Nakamura, Yukiko Kiniwa, Osamu Yamasaki, Satoshi Fukushima, Masahito Kawazu, Yutaka Suzuki, Hiroyoshi Nishikawa, Toyoyuki Hanazawa, Mizuo Ando, Takashi Inozume, Yosuke Togashi

Cancer research 84 ( 13 ) 2109 - 2122 2024年4月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

T cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T cell exhaustion, such as PD-1, can reinvigorate tumor-specific T cells and activate anti-tumor immunity in various types of cancer. Here, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA-sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed anti-tumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to PD-1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy.

DOI： 10.1158/0008-5472.CAN-23-0453

Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade 査読国際誌

Hidetoshi Hayashi, Kenji Chamoto, Ryusuke Hatae, Takashi Kurosaki, Yosuke Togashi, Kazuya Fukuoka, Megumi Goto, Yasutaka Chiba, Shuta Tomida, Takayo Ota, Koji Haratani, Takayuki Takahama, Junko Tanizaki, Takeshi Yoshida, Tsutomu Iwasa, Kaoru Tanaka, Masayuki Takeda, Tomoko Hirano, Hironori Yoshida, Hiroaki Ozasa, Yuichi Sakamori, Kazuko Sakai, Keiko Higuchi, Hitoshi Uga, Chihiro Suminaka, Toyohiro Hirai, Kazuto Nishio, Kazuhiko Nakagawa, Tasuku Honjo

Journal of Clinical Investigation 134 ( 7 ) 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Society for Clinical Investigation

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

DOI： 10.1172/jci168318

Abstract 7536: CD4+T cell exhaustion in the tumor microenvironment and antitumor immunity

Joji Nagasaki, Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Takashi Inozume, Yosuke Togashi

Cancer Research 84 ( 6_Supplement ) 7536 - 7536 2024年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：American Association for Cancer Research (AACR)

Abstract

Background: Immune checkpoint inhibitors (ICIs) exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). However, compared to CD8+ T cell exhaustion, the role of CD4+ T cell exhaustion in antitumor immunity remains unclear.

Methods and Results: From single-cell sequencing for tumor-infiltrating lymphocytes (TILs) from patients with melanoma and mouse models, we found that CXCL13, which is highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces PD-1+CXCR5+CD4+ follicular helper T (TFH)-like cell infiltration, which could contribute to antitumor immunity. Furthermore, a part of the TFH-like cells in the TME exhibits cytotoxicity and directly attacks MHC-II-expressing tumors. RNA velocity and latent time analysis in single-cell sequencing for melanoma TILs showed that the differentiation of TFH-like cells from the naive CD4+ T cells were different from that of other CD4+ T cells. In addition, the TFH-like cytotoxic CD4+ T cells were at the late stage of differentiation and some non-cytotoxic TFH-like cells might differentiate into TFH-like cytotoxic CD4+ T cells. We additionally found considerable overlapped clonotypes between the cytotoxic and non-cytotoxic clusters. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH-like cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively.

Conclusion: Our findings provide novel insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, which mediates antitumor immunity orchestrally with CD8+ T cells.

Citation Format: Joji Nagasaki, Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Takashi Inozume, Yosuke Togashi. CD4+T cell exhaustion in the tumor microenvironment and antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7536.

DOI： 10.1158/1538-7445.am2024-7536

Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment. 査読国際誌

Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Masahito Kawazu, Hiromichi Dansako, Yutaka Suzuki, Hiroyoshi Nishikawa, Takashi Inozume, Joji Nagasaki, Yosuke Togashi

Cell reports 43 ( 2 ) 113797 - 113797 2024年2月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.

DOI： 10.1016/j.celrep.2024.113797

Deletion of Pak1 in CD11c-Positive Cells Confers Resistance to Mouse Skin Carcinogenesis. 査読国際誌

Kazuhiro Okumura, Takao Morinaga, Megumi Saito, Yurika Tokunaga, Keisuke Otoyama, Sora Tanaka, Eriko Isogai, Masahito Kawazu, Yosuke Togashi, Kimi Araki, Yuichi Wakabayashi

The Journal of investigative dermatology 2024年2月

Hepatitis C virus NS5B triggers an MDA5-mediated innate immune response by producing dsRNA without the replication of viral genomes. 査読国際誌

Hiromichi Dansako, Masanori Ikeda, Yasuo Ariumi, Yosuke Togashi, Nobuyuki Kato

The FEBS journal 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

During the replication of viral genomes, RNA viruses produce double-stranded RNA (dsRNA), through the activity of their RNA-dependent RNA polymerases (RdRps) as viral replication intermediates. Recognition of viral dsRNA by host pattern recognition receptors - such as retinoic acid-induced gene-I (RIG-I)-like receptors and Toll-like receptor 3 - triggers the production of interferon (IFN)-β via the activation of IFN regulatory factor (IRF)-3. It has been proposed that, during the replication of viral genomes, each of RIG-I and melanoma differentiation-associated gene 5 (MDA5) form homodimers for the efficient activation of a downstream signalling pathway in host cells. We previously reported that, in the non-neoplastic human hepatocyte line PH5CH8, the RdRp NS5B derived from hepatitis C virus (HCV) could induce IFN-β expression by its RdRp activity without the actual replication of viral genomes. However, the exact mechanism by which HCV NS5B produced IFN-β remained unknown. In the present study, we first showed that NS5B derived from another Flaviviridae family member, GB virus B (GBV-B), also possessed the ability to induce IFN-β in PH5CH8 cells. Similarly, HCV NS5B, but not its G317V mutant, which lacks RdRp activity, induced the dimerization of MDA5 and subsequently the activation of IRF-3. Interestingly, immunofluorescence analysis showed that HCV NS5B produced dsRNA. Like HCV NS5B, GBV-B NS5B also triggered the production of dsRNA and subsequently the dimerization of MDA5. Taken together, our results show that HCV NS5B triggers an MDA5-mediated innate immune response by producing dsRNA without the replication of viral genomes in human hepatocytes.

DOI： 10.1111/febs.16980

Immunologic Significance of CD80/CD86 or Major Histocompatibility Complex-II Expression in Thymic Epithelial Tumors. 査読国際誌

Hideki Ikeda, Joji Nagasaki, Daiki Shimizu, Yuki Katsuya, Hidehito Horinouchi, Yukio Hosomi, Etsuko Tanji, Takekazu Iwata, Makiko Itami, Masahito Kawazu, Yuichiro Ohe, Takuji Suzuki, Yosuke Togashi

JTO clinical and research reports 4 ( 10 ) 100573 - 100573 2023年10月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Unresectable or recurrent thymic epithelial tumors (TETs) have a poor prognosis, and treatment options are limited. This study aimed to investigate the immunologic significance of CD80/CD86 or major histocompatibility complex class II (MHC-II) expression in TETs, as potential predictive biomarkers for immune checkpoint inhibitors (ICIs). METHODS: We analyzed CD80, CD86, MHC class I (MHC-I), and MHC-II expression in TETs using immunohistochemistry and investigated their association with T-cell infiltration or ICI efficacy. In addition, we generated CD80- or MHC-II-expressing mouse tumors, evaluated the effects of ICIs, and analyzed tumor-infiltrating lymphocytes. We also performed tumor-rechallenge experiments in vivo. RESULTS: We found that approximately 50% and 30% of TETs had high expression of CD80/CD86 and MHC-II in tumor cells, respectively, and that this expression was related to T-cell infiltration in clinical samples. In mouse models, both CD80 and MHC-II increase the effects of ICIs. In addition, senescent T cells and long-lived memory precursor effector T cells were significantly decreased and increased, respectively, in tumor-infiltrating lymphocytes from CD80-expressing tumors, and rechallenged tumors were completely rejected after the initial eradication of CD80-expressing tumors by programmed cell death protein 1 blockade. Indeed, patients with CD80-high thymic carcinoma had longer progression-free survival with anti-programmed cell death protein 1 monoclonal antibody. CONCLUSIONS: Half of the TETs had high expression of CD80/CD86 or MHC-II with high T-cell infiltration. These molecules could potentially increase the effects of ICIs, particularly inducing a durable response. CD80/CD86 and MHC-II can be predictive biomarkers of ICIs in TETs, promoting the development of drugs for such TETs.

DOI： 10.1016/j.jtocrr.2023.100573

Low frequency of intracranial progression in advanced NSCLC patients treated with cancer immunotherapies. 査読国際誌

Naoya Kemmotsu, Kiichiro Ninomiya, Kei Kunimasa, Takamasa Ishino, Joji Nagasaki, Yoshihiro Otani, Hiroyuki Michiue, Eiki Ichihara, Kadoaki Ohashi, Takako Inoue, Motohiro Tamiya, Kazuko Sakai, Youki Ueda, Hiromichi Dansako, Kazuto Nishio, Katsuyuki Kiura, Isao Date, Yosuke Togashi

International journal of cancer 2023年8月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Intracranial metastases are common in nonsmall-cell lung cancer (NSCLC) patients, whose prognosis is very poor. In addition, intracranial progression is common during systemic treatments due to the inability to penetrate central nervous system (CNS) barriers, whereas the intracranial effects of cancer immunotherapies remain unclear. We analyzed clinical data to evaluate the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies compared with those treated without PD-1 blockade therapies, and found that the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies was significantly lower than that in patients treated with cytotoxic chemotherapies. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade were suppressed. Accordingly, long-lived memory precursor effector T cells and antigen-specific T cells were increased by PD-1 blockade in intracranial lesions. However, intracranial rechallenged different tumors are not suppressed. Our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. If intracranial recurrence occurs during the treatment with PD-1 blockade therapies, aggressive local therapies could be worthwhile.

DOI： 10.1002/ijc.34700

Combination therapy with hydrogen peroxide and irradiation promotes an abscopal effect in mouse models. 査読国際誌

Naoya Kemmotsu, Li Zhu, Joji Nagasaki, Yoshihiro Otani, Youki Ueda, Hiromichi Dansako, Yue Fang, Isao Date, Yosuke Togashi

Cancer science 114 ( 10 ) 3848 - 3856 2023年7月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Hydrogen peroxide (H2 O2 ) induces oxidative stress and cytotoxicity, and can be used for treating cancers in combination with radiotherapy. A product comprising H2 O2 and sodium hyaluronate has been developed as a radiosensitizer. However, the effects of H2 O2 on antitumor immunity remain unclear. To investigate the effects of H2 O2 , especially the abscopal effect when combined with radiotherapy (RT), we implanted murine tumor cells simultaneously in two locations in mouse models: the hind limb and back. H2 O2 mixed with sodium hyaluronate was injected intratumorally, followed by irradiation only at the hind limb lesion. No treatment was administered to the back lesion. The H2 O2 /RT combination significantly reduced tumor growth at the noninjected/nonirradiated site in the back lesion, whereas H2 O2 or RT individually did not reduce tumor growth. Flow cytometric analyses of the tumor-draining lymph nodes in the injected/irradiated areas showed that the number of dendritic cells increased significantly with maturation in the H2 O2 /RT combination group. In addition, analyses of tumor-infiltrating lymphocytes showed that the number of CD8+ (cluster of differentiation 8) T cells and the frequency of IFN-γ+ (interferon gamma) CD8+ T cells were higher in the noninjected/nonirradiated tumors in the H2 O2 /RT group compared to those in the other groups. PD-1 (programmed death receptor 1) blockade further increased the antitumor effect against noninjected/nonirradiated tumors in the H2 O2 /RT group. Intratumoral injection of H2 O2 combined with RT therefore induces an abscopal effect by activating antitumor immunity, which can be further enhanced by PD-1 blockade. These findings promote the development of H2 O2 /RT therapy combined with cancer immunotherapies, even for advanced cancers.

DOI： 10.1111/cas.15911

High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects. 査読国際誌

Katsushige Kawase, Shusuke Kawashima, Joji Nagasaki, Takashi Inozume, Etsuko Tanji, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi

Cancer immunology research 11 ( 7 ) OF1-OF14 - 908 2023年4月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

IFNγ signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, conflicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resistance to immune checkpoint inhibitors owing to IFNγ signaling pathway defects may be primarily caused by reduced MHC-I expression rather than by the loss of inhibitory effects on cellular proliferation or decreased chemokine production. In particular, we found that chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment of a mouse model, with defects in IFNγ signaling pathways. Furthermore, we found a response to immune checkpoint inhibitors in a patient with JAK-negative head and neck squamous cell carcinoma whose HLA-I expression level was maintained. In addition, CRISPR screening to identify molecules associated with elevated MHC-I expression independent of IFNγ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFNγ signaling pathway defects are not always resistant to immune checkpoint inhibitors and highlight the importance of MHC-I expression among the pathways and the possibility of NF-κB-targeted therapies to overcome such resistance.

DOI： 10.1158/2326-6066.CIR-22-0815

Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity. 査読国際誌

Tomofumi Watanabe, Takamasa Ishino, Youki Ueda, Joji Nagasaki, Takuya Sadahira, Hiromichi Dansako, Motoo Araki, Yosuke Togashi

Cancer science 114 ( 5 ) 1859 - 1870 2023年2月

Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite deriving neoantigens. 査読国際誌

Takamasa Ishino, Shusuke Kawashima, Etsuko Tanji, Toshihide Ueno, Youki Ueda, Sadahisa Ogasawara, Kazuhito Sato, Hiroyuki Mano, Soichiro Ishihara, Naoya Kato, Masahito Kawazu, Yosuke Togashi

British journal of cancer 2023年2月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Identifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumour mutational burden reportedly tend to respond to ICIs. However, there are several conflicting data. Therefore, we focused on the original function of neoantigenic mutations and their impact on the tumour microenvironment (TME). METHODS: We evaluated 88 high-frequency microsatellite instability (MSI-H) colorectal cancers and analysed the function of the identified neoantigenic mutations and their influence on programmed cell death 1 (PD-1) blockade efficacy. The results were validated using The Cancer Genome Atlas (TCGA) datasets. RESULTS: We identified frameshift mutations in RNF43 as a common neoantigenic gene mutation in MSI-H tumours. However, loss-of-function RNF43 mutations induced noninflamed TME by activating the WNT/β-catenin signalling pathway. In addition, loss of RNF43 function induced resistance to PD-1 blockade even in neoantigen-rich tumours. TCGA dataset analyses demonstrated that passenger rather than driver gene mutations were related to the inflamed TME in diverse cancer types. CONCLUSIONS: We propose a novel concept of "paradoxical neoantigenic mutations" that can induce noninflamed TME through their original gene functions, despite deriving neoantigens, suggesting the significance of qualities as well as quantities in neoantigenic mutations.

DOI： 10.1038/s41416-023-02165-6

Editorial: Strategies to overcome tumor evasion and resistance to immunotherapies by targeting immune suppressor cells. 招待国際誌

Yu Saida, Satoshi Watanabe, Shohei Koyama, Yosuke Togashi, Toshiaki Kikuchi

Frontiers in oncology 13 1240926 - 1240926 2023年

Tumor-promoting function and regulatory landscape of PD-L2 in B-cell lymphoma. 査読国際誌

Sumito Shingaki, Junji Koya, Mitsuhiro Yuasa, Yuki Saito, Mariko Tabata, Marni B McClure, Seishi Ogawa, Kotoe Katayama, Yosuke Togashi, Seiya Imoto, Yasunori Kogure, Keisuke Kataoka

Leukemia 37 ( 2 ) 492 - 496 2022年12月

Resistance to immune checkpoint inhibitors and the tumor microenvironment. 招待査読国際誌

Shusuke Kawashima, Yosuke Togashi

Experimental dermatology 2022年11月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Immune checkpoint inhibitors (ICIs) have contributed significantly to the treatment of various types of cancer, including skin cancer. However, not all patients respond; some patients do not respond at all (primary resistance), while others experience recurrence after the initial response (acquired resistance). Therefore, overcoming ICI resistance is an urgent priority. Numerous ICI resistance mechanisms have been reported. They are seemingly quite complex, varying from patient to patient. However, most involve T-cell activation processes, especially in the tumor microenvironment (TME). ICIs exert their effects in the TME by reactivating suppressed T cells through inhibition of immune checkpoint molecules, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Thus, this review focuses on the resistance mechanisms based on the T-cell activation process. Here, we classify the main mechanisms of ICI resistance into three categories based on (1) antigen recognition, (2) T-cell migration and infiltration, and (3) effector functions of T cells. By identifying and understanding these resistance mechanisms individually, including unknown mechanisms, we seek to contribute to the development of novel treatments to overcome ICI resistance.

DOI： 10.1111/exd.14716

A variety of 'exhausted' T cells in the tumor microenvironment. 招待査読国際誌

Joji Nagasaki, Yosuke Togashi

International immunology 34 ( 11 ) 563 - 570 2022年10月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

In T cell biology, 'exhaustion' was initially described as a hyporesponsive state in CD8 + T cells during chronic infections. Recently, exhaustion has been recognized as a T-cell dysfunctional state in the tumor microenvironment (TME). The term 'exhaustion' is used mainly to refer to effector T cells with a reduced capacity to secrete cytokines and an increased expression of inhibitory receptors. The upregulation of exhaustion-related inhibitory receptors, including programmed cell death protein 1 (PD-1), in such T cells has been associated with the development of tumors, prompting the development of immune checkpoint inhibitors. In addition to CD8 + T cells, CD4 + T cells, including the regulatory T (Treg) cell subset, perform a wide variety of functions within the adaptive immune system. Upregulation of the same inhibitory receptors that are associated with CD8 + T-cell exhaustion has also been identified in CD4 + T cells in chronic infections and cancers, suggesting a similar CD4 + T-cell exhaustion phenotype. For instance, high expression of PD-1 has been observed in Treg cells in the TME, and such Treg cells can play an important role in the resistance to PD-1 blockade therapies. Furthermore, recent progress in single-cell RNA sequencing has shown that CD4 + T cells with cytotoxic activity are also vulnerable to exhaustion. In this review, we will discuss novel insights into various exhausted T-cell subsets, which could reveal novel therapeutic targets and strategies to induce a robust antitumor immune response.

DOI： 10.1093/intimm/dxac013

Mechanisms of resistance to immune checkpoint inhibitors. 招待査読国際誌

Joji Nagasaki, Takamasa Ishino, Yosuke Togashi

Cancer science 113 ( 10 ) 3303 - 3312 2022年10月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Immune checkpoint inhibitors (ICIs) are effective for various types of cancer, and their application has led to paradigm shifts in cancer treatment. While many patients can obtain clinical benefits from ICI treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. Thus, elucidating the resistance mechanisms is warranted to improve the clinical outcomes of ICI treatment. ICIs exert their antitumor effects by activating T cells in the tumor microenvironment. There are various resistance mechanisms, such as insufficient antigen recognition by T cells, impaired T-cell migration and/or infiltration, and reduced T-cell cytotoxicity, most of which are related to the T-cell activation process. Thus, we classify them into three main mechanisms: resistance mechanisms related to antigen recognition, T-cell migration and/or infiltration, and effector functions of T cells. In this review, we summarize these mechanisms of resistance to ICIs related to the T-cell activation process and progress in the development of novel therapies that can overcome resistance.

DOI： 10.1111/cas.15497

Mixed response to cancer immunotherapy is driven by intratumor heterogeneity and differential inter-lesion immune infiltration 査読

Takao Morinaga, Takashi Inozume, Masahito Kawazu, Youki Ueda, Nicolas Sax, Kazuo Yamashita, Shusuke Kawashima, Joji Nagasaki, Toshihide Ueno, Jason Lin, Yuuki Ohara, Takeshi Kuwata, Hiroki Yukami, Akihito Kawazoe, Kohei Shitara, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yu Kawahara, Yasuhiro Nakamura, Yukiko Kiniwa, Ayako Morita, Eiki Ichihara, Katsuyuki Kiura, Tomohiro Enokida, Makoto Tahara, Yoshinori Hasegawa, Hiroyuki Mano, Yutaka Suzuki, Hiroyoshi Nishikawa, Yosuke Togashi

Cancer Research Communications 2 ( 7 ) 739 - 753 2022年7月

担当区分：最終著者,　責任著者掲載種別：研究論文（学術雑誌）出版者・発行元：American Association for Cancer Research (AACR)

Abstract

Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TILs) demonstrated a significant difference in tumor clonality and TILs’ characteristics, especially exhausted T cell clonotypes, although a close relationship between the tumor cell and T cell clones were observed as a response of an overlapped exhausted T cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to PD-1 blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.

DOI： 10.1158/2767-9764.crc-22-0050

PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes. 査読国際誌

Joji Nagasaki, Takashi Inozume, Nicolas Sax, Ryo Ariyasu, Masakazu Ishikawa, Kazuo Yamashita, Masahito Kawazu, Toshihide Ueno, Takuma Irie, Etsuko Tanji, Takao Morinaga, Akiko Honobe, Takehiro Ohnuma, Mitsuru Yoshino, Takekazu Iwata, Katsushige Kawase, Keita Sasaki, Toyoyuki Hanazawa, Vitaly Kochin, Tatsuyoshi Kawamura, Hiroyuki Matsue, Masayuki Hino, Hiroyuki Mano, Yutaka Suzuki, Hiroyoshi Nishikawa, Yosuke Togashi

Cell reports 38 ( 5 ) 110331 - 110331 2022年2月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (Tex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the Tex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such Tex clonotypes, mainly from TDLNs.

DOI： 10.1016/j.celrep.2022.110331

Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. 査読国際誌

Shogo Kumagai, Shohei Koyama, Kota Itahashi, Tokiyoshi Tanegashima, Yi-Tzu Lin, Yosuke Togashi, Takahiro Kamada, Takuma Irie, Genki Okumura, Hidetoshi Kono, Daisuke Ito, Rika Fujii, Sho Watanabe, Atsuo Sai, Shota Fukuoka, Eri Sugiyama, Go Watanabe, Takuya Owari, Hitomi Nishinakamura, Daisuke Sugiyama, Yuka Maeda, Akihito Kawazoe, Hiroki Yukami, Keigo Chida, Yuuki Ohara, Tatsuya Yoshida, Yuki Shinno, Yuki Takeyasu, Masayuki Shirasawa, Kenta Nakama, Keiju Aokage, Jun Suzuki, Genichiro Ishii, Takeshi Kuwata, Naoya Sakamoto, Masahito Kawazu, Toshihide Ueno, Taisuke Mori, Naoya Yamazaki, Masahiro Tsuboi, Yasushi Yatabe, Takahiro Kinoshita, Toshihiko Doi, Kohei Shitara, Hiroyuki Mano, Hiroyoshi Nishikawa

Cancer cell 40 ( 2 ) 201 - 218 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

DOI： 10.1016/j.ccell.2022.01.001

Preoperative Chemoradiotherapy Plus Nivolumab Before Surgery in Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer Patients. 査読国際誌

Hideaki Bando, Yuichiro Tsukada, Koji Inamori, Yosuke Togashi, Shohei Koyama, Daisuke Kotani, Shota Fukuoka, Satoshi Yuki, Yoshito Komatsu, Shigenori Homma, Akinobu Taketomi, Mamoru Uemura, Takeshi Kato, Makoto Fukui, Masashi Wakabayashi, Naoki Nakamura, Motohiro Kojima, Hiroshi Kawachi, Richard Kirsch, Tsutomu Yoshida, Yutaka Suzuki, Akihiro Sato, Hiroyoshi Nishikawa, Masaaki Ito, Takayuki Yoshino

Clinical cancer research : an official journal of the American Association for Cancer Research 28 ( 6 ) 1136 - 1146 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Preoperative chemoradiotherapy (CRT) and surgical resection are standard treatment for locally advanced rectal cancer (LARC). Combining immune-checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC. METHODS: In phase I, we investigated the feasibility of sequentially-combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated. RESULTS: Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathological complete response (pCR) was centrally confirmed in 30% (11/37; 90% CI, 18 %-44%) and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30) (p=0.004, Fisher's exact test) were observed in those with PD-L1 tumor proportion score {greater than or equal to}1% and <1%, respectively; immunohistochemical staining was performed using pre-CRT samples. In 24 patients with MSS, pre-CRT samples were analyzed by flow cytometry; pCR rates of 78% (7/9) and 13% (2/15) (p=0.003, Fisher's exact test) were observed for CD8+-T cell / effector regulatory-T cell (CD8/eTreg) ratios of {greater than or equal to} 2.5 and < 2.5, respectively, in tumor-infiltrating lymphocytes. CONCLUSIONS: CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.

DOI： 10.1158/1078-0432.CCR-21-3213

Programmed Death-Ligand 1-Rich Premetastatic Niche in Adjuvant Chemotherapy. 招待査読国際誌

Hiromasa Yamamoto, Yosuke Togashi

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 17 ( 1 ) 10 - 12 2022年1月

Transcript-targeted analysis reveals isoform alterations and double-hop fusions in breast cancer. 査読国際誌

Shinichi Namba, Toshihide Ueno, Shinya Kojima, Kenya Kobayashi, Katsushige Kawase, Yosuke Tanaka, Satoshi Inoue, Fumishi Kishigami, Shusuke Kawashima, Noriko Maeda, Tomoko Ogawa, Shoichi Hazama, Yosuke Togashi, Mizuo Ando, Yuichi Shiraishi, Hiroyuki Mano, Masahito Kawazu

Communications biology 4 ( 1 ) 1320 - 1320 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although transcriptome alteration is an essential driver of carcinogenesis, the effects of chromosomal structural alterations on the cancer transcriptome are not yet fully understood. Short-read transcript sequencing has prevented researchers from directly exploring full-length transcripts, forcing them to focus on individual splice sites. Here, we develop a pipeline for Multi-Sample long-read Transcriptome Assembly (MuSTA), which enables construction of a transcriptome from long-read sequence data. Using the constructed transcriptome as a reference, we analyze RNA extracted from 22 clinical breast cancer specimens. We identify a comprehensive set of subtype-specific and differentially used isoforms, which extended our knowledge of isoform regulation to unannotated isoforms including a short form TNS3. We also find that the exon-intron structure of fusion transcripts depends on their genomic context, and we identify double-hop fusion transcripts that are transcribed from complex structural rearrangements. For example, a double-hop fusion results in aberrant expression of an endogenous retroviral gene, ERVFRD-1, which is normally expressed exclusively in placenta and is thought to protect fetus from maternal rejection; expression is elevated in several TCGA samples with ERVFRD-1 fusions. Our analyses provide direct evidence that full-length transcript sequencing of clinical samples can add to our understanding of cancer biology and genomics in general.

DOI： 10.1038/s42003-021-02833-4

Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape. 査読国際誌

Yoshiko Takeuchi, Tokiyoshi Tanegashima, Eiichi Sato, Takuma Irie, Atsuo Sai, Kota Itahashi, Shogo Kumagai, Yasuko Tada, Yosuke Togashi, Shohei Koyama, Esra A Akbay, Takahiro Karasaki, Keisuke Kataoka, Soichiro Funaki, Yasushi Shintani, Izumi Nagatomo, Hiroshi Kida, Genichiro Ishii, Tomohiro Miyoshi, Keiju Aokage, Kazuhiro Kakimi, Seishi Ogawa, Meinoshin Okumura, Masatoshi Eto, Atsushi Kumanogoh, Masahiro Tsuboi, Hiroyoshi Nishikawa

Science immunology 6 ( 65 ) eabc6424 2021年11月

TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment. 査読国際誌

Shusuke Kawashima, Takashi Inozume, Masahito Kawazu, Toshihide Ueno, Joji Nagasaki, Etsuko Tanji, Akiko Honobe, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Tomonori Kawasaki, Yukiko Kiniwa, Osamu Yamasaki, Satoshi Fukushima, Yuzuru Ikehara, Hiroyuki Mano, Yutaka Suzuki, Hiroyoshi Nishikawa, Hiroyuki Matsue, Yosuke Togashi

Journal for immunotherapy of cancer 9 ( 11 ) 2021年11月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. METHODS: We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort. RESULTS: Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance. CONCLUSIONS: The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.

DOI： 10.1136/jitc-2021-003134

HLA Class I analysis provides insight into the genetic and epigenetic background of immune evasion in colorectal cancer with high microsatellite instability. 査読国際誌

Masahito Kawazu, Toshihide Ueno, Koichi Saeki, Nicolas Sax, Yosuke Togashi, Takayuki Kaneseki, Keigo Chida, Fumishi Kishigami, Kazuhito Sato, Shinya Kojima, Masafumi Otsuka, Akihito Kawazoe, Hitomi Nishinakamura, Yuka Maeda, Yoko Yamamoto, Kazuo Yamashita, Satoshi Inoue, Tokiyoshi Tanegashima, Daisuke Matsubara, Kenta Tane, Yosuke Tanaka, Hisae Iinuma, Yojiro Hashiguchi, Shoichi Hazama, Seik-Soon Khor, Katsushi Tokunaga, Masahiro Tsuboi, Toshiro Niki, Masatoshi Eto, Kohei Shitara, Toshihiko Torigoe, Soichiro Ishihara, Hiroyuki Aburatani, Hiroshi Haeno, Hiroyoshi Nishikawa, Hiroyuki Mano

Gastroenterology 162 ( 3 ) 799 - 812 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers (MSI-H CRCs) using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 (50%) tumors and loss of 61 alleles in 21 (18%) tumors. Based on the integrated analysis that enabled the immunological subclassification of MSI-H CRCs, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.

DOI： 10.1053/j.gastro.2021.10.010

Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1. 査読国際誌

Junji Koya, Yuki Saito, Takuro Kameda, Yasunori Kogure, Mitsuhiro Yuasa, Joji Nagasaki, Marni B McClure, Sumito Shingaki, Mariko Tabata, Yuki Tahira, Keiichi Akizuki, Ayako Kamiunten, Masaaki Sekine, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Akira Kitanaka, Nobuaki Nakano, Atae Utsunomiya, Yosuke Togashi, Seishi Ogawa, Kazuya Shimoda, Keisuke Kataoka

Blood cancer discovery 2 ( 5 ) 450 - 467 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Premalignant clonal expansion of human T-cell leukemia virus type-1 (HTLV-1)-infected cells occurs before viral carcinogenesis. Here we characterize premalignant cells and the multicellular ecosystem in HTLV-1 infection with and without adult T-cell leukemia/lymphoma (ATL) by genome sequencing and single-cell simultaneous transcriptome and T/B-cell receptor sequencing with surface protein analysis. We distinguish malignant phenotypes caused by HTLV-1 infection and leukemogenesis and dissect clonal evolution of malignant cells with different clinical behavior. Within HTLV-1-infected cells, a regulatory T-cell phenotype associates with premalignant clonal expansion. We also delineate differences between virus- and tumor-related changes in the nonmalignant hematopoietic pool, including tumor-specific myeloid propagation. In a newly generated conditional knockout mouse model recapitulating T-cell-restricted CD274 (encoding PD-L1) gene lesions found in ATL, we demonstrate that PD-L1 overexpressed by T cells is transferred to surrounding cells, leading to their PD-L1 upregulation. Our findings provide insights into clonal evolution and immune landscape of multistep virus carcinogenesis. Significance: Our multimodal single-cell analyses comprehensively dissect the cellular and molecular alterations of the peripheral blood in HTLV-1 infection, with and without progression to leukemia. This study not only sheds light on premalignant clonal expansion in viral carcinogenesis, but also helps to devise novel diagnostic and therapeutic strategies for HTLV-1-related disorders.

DOI： 10.1158/2643-3230.BCD-21-0044

Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer. 査読国際誌

Koji Inamori, Yosuke Togashi, Shota Fukuoka, Kiwamu Akagi, Kouetsu Ogasawara, Takuma Irie, Daisuke Motooka, Yoichi Kobayashi, Daisuke Sugiyama, Motohiro Kojima, Norihiko Shiiya, Shota Nakamura, Shoichi Maruyama, Yutaka Suzuki, Masaaki Ito, Hiroyoshi Nishikawa

JCI insight 6 ( 9 ) 2021年5月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Patients with colorectal cancers (CRCs) generally exhibit improved survival through intensive lymph node (LN) dissection. However, recent progress in cancer immunotherapy revisits the potential importance of regional LNs, where T cells are primed to attack tumor cells. To elucidate the role of regional LN, we investigated the immunological status of non-metastatic regional LN lymphocytes (LNLs) in comparison with those in the tumor microenvironment (tumor-infiltrating lymphocytes; TILs) using flow cytometry and next-generation sequencing. LNLs comprised an intermediate level of the effector T cell population between peripheral blood lymphocytes (PBLs) and TILs. Significant overlap of the T-cell receptor (TCR) repertoire was observed in microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) CRCs with high tumor mutation burden (TMB), although limited TCRs were shared between non-metastatic LNs and primary tumors in microsatellite stable (MSS)/MMR proficient (pMMR) CRC patients with low TMB. In line with the overlap of the TCR repertoire, an excessive LN dissection did not provide a positive impact on long-term prognosis in our MSI-H/dMMR CRC cohort (n =130). We propose that regional LNs play an important role in antitumor immunity, particularly in MSI-H/dMMR CRCs with high TMB, requiring to be careful of excessive non-metastatic LN dissection in MSI-H/dMMR CRC patients.

DOI： 10.1172/jci.insight.137365

Aging, cancer, and antitumor immunity. 招待査読

Hideki Ikeda, Yosuke Togashi

International journal of clinical oncology 2021年3月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Aging leads to numerous changes that affect many components of the immune system, called "immunosenescence". Indeed, elderly individuals exhibit dysregulated immune responses against pathogens, poor responses to vaccination, and increased susceptibility to many diseases including cancer, autoimmune disorders, and other chronic inflammatory diseases. Despite progressed understanding of immunosenescence, its detailed mechanisms are still not fully understood. With advances in medicine, the population of older cancer patients is expected to rapidly increase in the coming years. Cancer immunotherapies, including immune checkpoint inhibitors (ICIs), have been shown to be effective for multiple cancer types, whereas to date, few specific data for elderly individuals have been published. Some systemic reviews have demonstrated that ICIs exhibit similar efficacy in older cancer patients, but they seem to be less effective in very old patients. In addition, toxicities might be more frequently observed in such patients. Here, we provide a summary to better understand immunosenescence and an overview of its relationship with cancer and antitumor immunity, including the efficacy and toxicity of ICIs.

DOI： 10.1007/s10147-021-01913-z

HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs. 査読国際誌

Sho Watanabe, Yasushi Goto, Hiroyuki Yasuda, Takashi Kohno, Noriko Motoi, Yuichiro Ohe, Hiroyoshi Nishikawa, Susumu S Kobayashi, Kazuyoshi Kuwano, Yosuke Togashi

Thoracic cancer 12 ( 5 ) 631 - 642 2021年3月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third-generation EGFR-TKIs overcome this resistance by selectively inhibiting EGFR with EGFR-TKI-sensitizing and T790M mutations, acquired resistance to third-generation EGFR-TKIs invariably develops. METHODS: Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M-mutated NSCLC patient who had progressed after a third-generation EGFR-TKI, TAS-121. EGFR-mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR-TKIs and a heat shock protein 90 (HSP90) inhibitor. RESULTS: NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M-mutated cell line was sensitive to osimertinib or TAS-121 in vitro, EGFR-overexpressing cell lines displayed resistance to these EGFR-TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third-generation EGFR-TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines. CONCLUSIONS: EGFR amplification confers resistance to third-generation EGFR-TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification-mediated resistance.

DOI： 10.1111/1759-7714.13839

Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens. 査読国際誌

Yukie Kashima, Yosuke Togashi, Shota Fukuoka, Takahiro Kamada, Takuma Irie, Ayako Suzuki, Yoshiaki Nakamura, Kohei Shitara, Tatsunori Minamide, Taku Yoshida, Naofumi Taoka, Tatsuya Kawase, Teiji Wada, Koichiro Inaki, Masataka Chihara, Yukihiko Ebisuno, Sakiyo Tsukamoto, Ryo Fujii, Akihiro Ohashi, Yutaka Suzuki, Katsuya Tsuchihara, Hiroyoshi Nishikawa, Toshihiko Doi

Scientific reports 11 ( 1 ) 341 - 341 2021年1月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.

DOI： 10.1038/s41598-020-79385-w

Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants. 査読国際誌

Ayumu Arakawa, Hitoshi Ichikawa, Takashi Kubo, Noriko Motoi, Tadashi Kumamoto, Miho Nakajima, Kan Yonemori, Emi Noguchi, Kuniko Sunami, Kouya Shiraishi, Hiroki Kakishima, Hiroshi Yoshida, Tomoro Hishiki, Naonori Kawakubo, Takafumi Kuroda, Takako Kiyokawa, Kyosuke Yamada, Nozomu Yanaihara, Kazuaki Takahashi, Aikou Okamoto, Shinsuke Hirabayashi, Daisuke Hasegawa, Atsushi Manabe, Kentaro Ono, Masaki Matsuoka, Yasuhito Arai, Yosuke Togashi, Tatsuhiro Shibata, Hiroyoshi Nishikawa, Kazunori Aoki, Noboru Yamamoto, Takashi Kohno, Chitose Ogawa

The New England journal of medicine 384 ( 1 ) 42 - 50 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).

DOI： 10.1056/NEJMoa2030391

Heterogeneity in congenital melanocytic nevi contributes to multicentric melanomagenesis. 査読国際誌

Akiko Honobe, Kazuko Sakai, Yosuke Togashi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Kazuto Nishio, Takashi Inozume

Journal of dermatological science 100 ( 3 ) 217 - 219 2020年12月

The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. 査読国際誌

Shogo Kumagai, Yosuke Togashi, Takahiro Kamada, Eri Sugiyama, Hitomi Nishinakamura, Yoshiko Takeuchi, Kochin Vitaly, Kota Itahashi, Yuka Maeda, Shigeyuki Matsui, Takuma Shibahara, Yasuho Yamashita, Takuma Irie, Ayaka Tsuge, Shota Fukuoka, Akihito Kawazoe, Hibiki Udagawa, Keisuke Kirita, Keiju Aokage, Genichiro Ishii, Takeshi Kuwata, Kenta Nakama, Masahito Kawazu, Toshihide Ueno, Naoya Yamazaki, Koichi Goto, Masahiro Tsuboi, Hiroyuki Mano, Toshihiko Doi, Kohei Shitara, Hiroyoshi Nishikawa

Nature immunology 21 ( 11 ) 1346 - 1358 2020年11月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1+CD8+ T cells relative to that of PD-1+ regulatory T (Treg) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8+ T cells and Treg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1+CD8+ T cells and enhanced PD-1+ Treg cell-mediated immunosuppression. A profound reactivation of effector PD-1+CD8+ T cells rather than PD-1+ Treg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.

DOI： 10.1038/s41590-020-0769-3

Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial. 査読国際誌

Hidetoshi Hayashi, Yuichi Takiguchi, Hironobu Minami, Kohei Akiyoshi, Yoshihiko Segawa, Hiroki Ueda, Yasuo Iwamoto, Chihiro Kondoh, Koji Matsumoto, Shin Takahashi, Hisateru Yasui, Toshiyuki Sawa, Yusuke Onozawa, Yasutaka Chiba, Yosuke Togashi, Yoshihiko Fujita, Kazuko Sakai, Shuta Tomida, Kazuto Nishio, Kazuhiko Nakagawa

JAMA oncology 6 ( 12 ) 1931 - 1938 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial Registration: UMIN Identifier: UMIN000016794.

DOI： 10.1001/jamaoncol.2020.4643

The critical role of CD4+ T cells in PD-1 blockade against MHC-II-expressing tumors such as classic Hodgkin lymphoma. 査読国際誌

Joji Nagasaki, Yosuke Togashi, Takeaki Sugawara, Makiko Itami, Nobuhiko Yamauchi, Junichiro Yuda, Masato Sugano, Yuuki Ohara, Yosuke Minami, Hirohisa Nakamae, Masayuki Hino, Masahiro Takeuchi, Hiroyoshi Nishikawa

Blood advances 4 ( 17 ) 4069 - 4082 2020年9月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II-expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II-expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I-MHC-II+ tumors but not on MHC-I-MHC-II- tumors, in a cytotoxic CD4+ T-cell-dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II-expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II-expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.

DOI： 10.1182/bloodadvances.2020002098

Enhanced tumor response to radiotherapy after PD-1 blockade in metastatic gastric cancer. 査読

Akinori Sasaki, Yoshiaki Nakamura, Yosuke Togashi, Hirofumi Kuno, Hidehiro Hojo, Shunichiro Kageyama, Naoki Nakamura, Kenji Takashima, Tomohiro Kadota, Yusuke Yoda, Saori Mishima, Kentaro Sawada, Daisuke Kotani, Akihito Kawazoe, Yasutoshi Kuboki, Hiroya Taniguchi, Takashi Kojima, Toshihiko Doi, Takayuki Yoshino, Tomonori Yano, Tatsushi Kobayashi, Tetsuo Akimoto, Hiroyoshi Nishikawa, Kohei Shitara

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 23 ( 5 ) 893 - 903 2020年9月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Immune checkpoint inhibitors may enhance the efficacy of radiotherapy (RT) in cancer treatment but the effect remains unknown in metastatic gastric cancer (mGC). This study aimed to compare the tumor shrinkage by palliative RT for mGC patients with or without previous exposure to anti-PD-1 therapy. METHODS: Data of 36 mGC patients who had received palliative RT from April 2013 to May 2019 were analyzed. Primary tumor responses were evaluated through a volumetric measurement-based method using computed tomography (CT) and endoscopic responses were evaluated in patients who underwent endoscopy before and after RT. Tumor microenvironment (TME) immune status was investigated by analyzing tumor-infiltrating lymphocytes by flow cytometry. RESULTS: Among 36 patients, 18 had previous exposure to anti-PD-1 before RT showing no significant differences in baseline characteristics with the other 18 patients without exposure to anti-PD-1 treatment. Tumor responses were observed in 28% (5/18) and none (0/18) in the anti-PD-1-exposed vs. naïve group, respectively (P = 0.045). Five out of eight patients in the anti-PD-1-exposed group, who underwent endoscopy after RT showed partial response, but none in the anti-PD-1-naïve patients showed response (P = 0.026). Increase in the CD8+ T cell/effector regulatory T cell ratio in TILs after anti-PD-1 therapy was noted in three responders to RT, but not in the other three non-responders. CONCLUSIONS: Prior exposure to anti-PD-1 therapy increases tumor response to RT. Immune profiling suggests that anti-PD-1 therapy may enhance the efficacy of RT by immunoactivation in the TME.

DOI： 10.1007/s10120-020-01058-4

Multicenter phase 1/2 Trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP Trial). 査読国際誌

Akihito Kawazoe, Yasutoshi Kuboki, Eiji Shinozaki, Hiroki Hara, Tomohiro Nishina, Yoshito Komatsu, Satoshi Yuki, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Takeshi Kuwata, Masahito Kawazu, Hiroyuki Mano, Yosuke Togashi, Hiroyoshi Nishikawa, Takayuki Yoshino

Clinical cancer research : an official journal of the American Association for Cancer Research 26 ( 22 ) 5887 - 5894 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: This is a phase 1/2 trial of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: Phase 1 was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240mg to 480 mg twice daily) with 200mg pembrolizumab every 3 weeks. Phase 2 included cohort A (n = 10, microsatellite instability high) and cohort B (n = 40, microsatellite stable). The primary endpoint was immune-related objective response rate (irORR). PD-L1 combined positive score (CPS), genomic profiles and the consensus molecular subtypes (CMS) of colorectal cancer were assessed. RESULTS: A total of 55 patients were enrolled in this study. In phase 1, no patients experienced dose-limiting toxicities and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS <1, 1≤ CPS <10 and CPS ≥10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3% and 33.3% in CMS1, CMS2, CMS3 and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B. CONCLUSIONS: Napabucasin with pembrolizumab showed anti-tumor activity with acceptable toxicities for MSS mCRC patients as well as MSI-H mCRC, although it did not meet the primary end point.

DOI： 10.1158/1078-0432.CCR-20-1803

An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells. 査読国際誌

Shogo Kumagai, Yosuke Togashi, Chika Sakai, Akihito Kawazoe, Masahito Kawazu, Toshihide Ueno, Eiichi Sato, Takeshi Kuwata, Takahiro Kinoshita, Masami Yamamoto, Sachiyo Nomura, Tetsuya Tsukamoto, Hiroyuki Mano, Kohei Shitara, Hiroyoshi Nishikawa

Immunity 53 ( 1 ) 187 - 203 2020年7月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB.

DOI： 10.1016/j.immuni.2020.06.016

Association between the mutational smoking signature and the immune microenvironment in lung adenocarcinoma. 査読国際誌

Kei Sato, Sachiyo Mimaki, Riu Yamashita, Yosuke Togashi, Tomoyuki Naito, Hibiki Udagawa, Shinya Katsumata, Shoko Nakasone, Tomohiro Miyoshi, Kenta Tane, Keiju Aokage, Masato Sugano, Motohiro Kojima, Satoshi Fujii, Takeshi Kuwata, Atsushi Ochiai, Koichi Goto, Masahiro Tsuboi, Katsuya Tsuchihara, Genichiro Ishii

Lung cancer (Amsterdam, Netherlands) 147 12 - 20 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Mutational signatures associated with tobacco smoking (mutational smoking signatures: SS) are characterized mainly by C > A mutations. The aim of this study was to characterize the association between the tumor immune microenvironment and the SS in lung adenocarcinoma. METHODS: Lung adenocarcinomas surgically resected from 96 patients, for which whole exome sequencing data was available, were included in the study. We extracted the SS from whole exome sequencing data, calculated the weights of SS using deconstructSigs, and compared the clinicopathological features of SS positive (SS+) and negative (SS-) adenocarcinomas. We selected 18 tumor pairs from SS + and SS- adenocarcinomas (sex, EGFR mutation, and tumor size-matched) and examined the expression of five immune markers (CD20, CD8, FOXP3, CD204, and PD-L1) by immunohistochemistry. RESULTS: Of 96 specimens, there were 33 (34 %) SS + adenocarcinoma tumors. The smoking index significantly correlated with the weight of the SS (R = 0.43). Between SS + and SS- tumors, there was no significant difference in clinicopathological factors excluding smoking history. Immunohistochemistry revealed that the number of FOXP3 + T cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 58 vs. 36, p < 0.01). Also, the number of CD20 + B cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 77 vs. 29, p < 0.01); however; these phenomena could not be confirmed when stratified by smoking history. CONCLUSION: In lung adenocarcinoma, SS is associated with an immunosuppressive tumor microenvironment.

DOI： 10.1016/j.lungcan.2020.06.029

Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). 査読国際誌

Shota Fukuoka, Hiroki Hara, Naoki Takahashi, Takashi Kojima, Akihito Kawazoe, Masako Asayama, Takako Yoshii, Daisuke Kotani, Hitomi Tamura, Yuichi Mikamoto, Nami Hirano, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Takeshi Kuwata, Yosuke Togashi, Hiroyoshi Nishikawa, Kohei Shitara

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38 ( 18 ) 2053 - 2061 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: This is a phase Ib trial of regorafenib plus nivolumab for gastric and colorectal cancer. PATIENTS AND METHODS: Enrolled patients received regorafenib plus nivolumab in a dose-finding part to estimate the maximum tolerated dose. Additional patients were enrolled in a dose-expansion part. Regorafenib of 80-160 mg was administered once daily for 21 days on/7 days off with nivolumab 3 mg/kg every 2 weeks. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks to estimate the recommended dose. RESULTS: Fifty patients (25 each with gastric and colorectal cancer) were enrolled. All patients had received ≥ 2 previous lines of chemotherapy, including anti-angiogenetic inhibitors in 96% of patients. Seven patients with gastric cancer had previously been treated with immune checkpoint inhibitors. One patient had microsatellite instability-high colorectal cancer, whereas the remaining patients had microsatellite stable or mismatch repair-proficient tumors. Three DLTs (grade 3 colonic perforation, maculopapular rash, and proteinuria) were observed with regorafenib 160 mg; none were observed with 80 or 120 mg. During the dose-expansion part, regorafenib dose was reduced from 120 to 80 mg because of frequent maculopapular rash. The common grade ≥ 3 treatment-related adverse events were rash (12%), proteinuria (12%), and palmar-plantar erythrodysesthesia (10%). Objective tumor response was observed in 20 patients (40%), including 11 with gastric cancer (44%) and 9 with colorectal cancer (36%). Median progression-free survival was 5.6 and 7.9 months in patients with gastric and colorectal cancer, respectively. CONCLUSION: The combination of regorafenib 80 mg plus nivolumab had a manageable safety profile and encouraging antitumor activity in patients with gastric and colorectal cancer, which warrants additional investigations in larger cohorts.

DOI： 10.1200/JCO.19.03296

TENERGY: multicenter phase II study of Atezolizumab monotherapy following definitive Chemoradiotherapy with 5-FU plus Cisplatin in patients with unresectable locally advanced esophageal squamous cell carcinoma. 査読国際誌

Hideaki Bando, Daisuke Kotani, Takahiro Tsushima, Hiroki Hara, Shigenori Kadowaki, Ken Kato, Keisho Chin, Kensei Yamaguchi, Shun-Ichiro Kageyama, Hidehiro Hojo, Masaki Nakamura, Hidenobu Tachibana, Masashi Wakabayashi, Miki Fukutani, Yosuke Togashi, Nozomu Fuse, Hiroyoshi Nishikawa, Takashi Kojima

BMC cancer 20 ( 1 ) 336 - 336 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy (CRT) using 5-FU plus cisplatin. However, complete response (CR) rates are low at 11-25%, resulting in 9-10 months of median overall survival (OS). An improved therapeutic efficacy by combining immunotherapy with radiation has been reported in patients with locally advanced non-small cell lung cancer. The results using ESCC cell lines suggest sequential treatment with anti-PD-L1 agents soon after completion of CRT is the most effective combination. METHODS: TENERGY trial is a multicenter, phase II, proof-of-concept study to assess the efficacy and safety of atezolizumab following definitive CRT in patients with locally advanced ESCC. The main inclusion criteria are unresectable locally advanced ESCC without distant metastasis, completion of 60 Gy of radiation plus two concomitant cycles of chemotherapy (cisplatin 70 mg/m2 on day 1 and 5-FU 700 mg/m2 on days 1-4, every 28 days), and adequate organ function. Within 6 weeks after CRT, participants will start taking 1200 mg of atezolizumab every three weeks and continue until 12 months or disease progression. The primary endpoint is the confirmed CR rate by the investigator's assessment. Secondary endpoints include overall response rate, progression-free survival (PFS), OS, adverse events, and confirmed CR rate by central assessment. We will enroll 50 patients (40 with primary locally advanced ESCC and 10 with postoperative locoregionally recurrent ESCC). We will obtain biopsies from the primary site and will collect blood at 3 time points (before CRT, after CRT, and four weeks after the start of atezolizumab) for an exploratory biomarker study. We will analyze the phenotype of immune-competent cells, neoantigens, tumor mutational burden, PD-L1 status, and Human Leukocyte Antigen haplotyping. DISCUSSION: The synergistic efficacies of the sequential combination of CRT and atezolizumab should improve the CR rate, resulting in survival improvement for patients with unresectable locally advanced ESCC. Because CRT is a standard treatment option for patients with early stage to locally advanced ESCC, the sequential combination of CRT and atezolizumab has the potential to change the standard ESCC treatments. TRIAL REGISTRATION: UMIN000034373, 10/04/2018 and EPOC1802.

DOI： 10.1186/s12885-020-06716-5

The potential application of PD-1 blockade therapy for early-stage biliary tract cancer. 査読国際誌

Kumiko Umemoto, Yosuke Togashi, Yasuhito Arai, Hiromi Nakamura, Shinichiro Takahashi, Tokiyoshi Tanegashima, Mikiya Kato, Tsubasa Nishikawa, Daisuke Sugiyama, Motohiro Kojima, Naoto Gotohda, Takeshi Kuwata, Masafumi Ikeda, Tatsuhiro Shibata, Hiroyoshi Nishikawa

International immunology 32 ( 4 ) 273 - 281 2020年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Biliary tract cancer (BTC) is an aggressive cancer with a poor prognosis partially due to the limited success in developing novel therapies, including molecularly targeted therapies and immunotherapies. Programmed cell death-1 (PD-1) blockade therapy is less effective against BTCs, necessitating further studies to understand the detailed immunological status of the tumor microenvironment (TME) in BTC. Here, we examined the immunological status of the TME in 37 BTCs with early- to late-stage disease, especially focusing on PD-1+CD8+ T cells. PD-1+CD8+ T cells, which are reportedly associated with the clinical response to PD-1 blockade therapy, were frequently observed in early-stage BTC and decreased with disease progression. Imaging mass cytometry for representative PD-1+CD8+TIL-high and -low patients demonstrated that tumor-infiltrating PD-1+CD8+ T cells were localized adjacent to tumor cells, whereas PD-1-CD8+ T cells were detected mainly in the stroma of the TME. In a mouse model, PD-1 expression by tumor-infiltrating CD8+ T cells was higher in smaller tumors and decreased with tumor growth. Consequently, large tumors became resistant to PD-1 blockade, while small tumors containing higher numbers of PD-1+CD8+ T cells were sensitive. We propose the important role of tumor-infiltrating PD-1+CD8+ T cells in anti-tumor immunity and the potential application of PD-1 blockade therapy for early-stage BTC.

DOI： 10.1093/intimm/dxz080

Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non–small cell lung cancer 査読国際誌

Sugiyama E, Togashi Y, Takeuchi Y, Shinya S, Tada Y, Kataoka K, Tane K, Sato E, Ishii G, Goto K, Shintani Y, Okumura M, Tsuboi M, Nishikawa H

Science Immunology 5 ( 43 ) 2020年1月

Multiple modalities of single cell analyses to evaluate the tumor microenvironment in clinical specimens 査読

Yukie Kashima, Shota Fukuoka, Yosuke Togashi, Takahiro Kamada, Ayako Suzuki, Yoshiaki Nakamura, Kohei Shitara, Akihiro Ohashi, Taku Yoshida, Naofumi Taoka, Tatsuya Kawase, Teiji Wada, Kocihiro Inaki, Masataka Chihara, Yutaka Suzuki, Katsuya Tsuchihara, Susumu S. Kobayashi, Hiroyoshi Nishikawa, Toshihiko Doi

MOLECULAR CANCER THERAPEUTICS 18 ( 12 ) 2019年12月

Clinical and immune profiling for cancer of unknown primary site. 査読

Haratani K, Hayashi H, Takahama T, Nakamura Y, Tomida S, Yoshida T, Chiba Y, Sawada T, Sakai K, Fujita Y, Togashi Y, Tanizaki J, Kawakami H, Ito A, Nishio K, Nakagawa K

Journal for immunotherapy of cancer 7 ( 1 ) 251 2019年9月

Selective inhibition of low-affinity memory CD8⁺ T cells by corticosteroids. 査読国際誌

Tokunaga A, Sugiyama D, Maeda Y, Warner AB, Panageas KS, Ito S, Togashi Y, Sakai C, Wolchok JD, Nishikawa H

The Journal of experimental medicine 216 ( 12 ) 2701 - 2713 2019年9月

Analysis of the Tumor Reactivity of Tumor-Infiltrating Lymphocytes in a Metastatic Melanoma Lesion that Lost Major Histocompatibility Complex Class I Expression after Anti-PD-1 Therapy. 査読国際誌

Takashi Inozume, Tomonori Yaguchi, Ryo Ariyasu, Yosuke Togashi, Takehiro Ohnuma, Akiko Honobe, Hiroyoshi Nishikawa, Yutaka Kawakami, Tatsuyoshi Kawamura

The Journal of investigative dermatology 139 ( 7 ) 1490 - 1496 2019年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Major histocompatibility complex class I loss due to the abnormality of β2-microglobulin gene is one of the mechanisms underlying delayed relapses in melanoma patients long after the initial positive responses to anti-PD-1 therapy. However, the tumor-specific reactivity of tumor-infiltrating lymphocytes in tumor lesions that lost major histocompatibility complex class I expression has not been well evaluated. We report the case of a 55-year-old woman with two metastatic melanoma lesions. After a 12-month period of successful tumor suppression by anti-PD-1 antibody therapy, one lesion started to grow again. We resected both lesions and examined the tumor cells and tumor-infiltrating lymphocytes. The shrinking lesion consisted of necrotic tissue and macrophages, and the enlarged lesion consisted of both necrotic tissue and viable tumor cells. The tumor cells completely lost major histocompatibility complex class I expression, but it was restored upon retroviral transduction of the normal β2-microglobulin gene. When we checked the tumor-specific reactivity of tumor-infiltrating lymphocytes derived from the relapsing lesion, we found that these tumor-infiltrating lymphocytes failed to recognize the native tumor cells derived from the lesion, but strongly recognized the major histocompatibility complex class-I-recovered cells by β2-microglobulin transduction. Our report emphasizes the limitations of T-cell-based immunotherapy and highlights the importance of developing alternative strategies for such cases.

DOI： 10.1016/j.jid.2019.01.007

Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity. 査読

Tanegashima T, Togashi Y, Azuma K, Kawahara A, Ideguchi K, Sugiyama D, Kinoshita F, Akiba J, Kashiwagi E, Takeuchi A, Irie T, Tatsugami K, Hoshino T, Eto M, Nishikawa H

Clinical cancer research : an official journal of the American Association for Cancer Research 25 ( 15 ) 4808 - 4819 2019年5月

PD-1⁺ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. 査読国際誌

Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, Morikawa H, Kawazoe A, Kinoshita T, Shitara K, Sakaguchi S, Nishikawa H

Proceedings of the National Academy of Sciences of the United States of America 116 ( 20 ) 9999 - 10008 2019年4月

Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer. 査読国際誌

Satomi Watanabe, Hidetoshi Hayashi, Koji Haratani, Shigeki Shimizu, Junko Tanizaki, Kazuko Sakai, Hisato Kawakami, Kimio Yonesaka, Junji Tsurutani, Yosuke Togashi, Kazuto Nishio, Akihiko Ito, Kazuhiko Nakagawa

Cancer science 110 ( 1 ) 52 - 60 2019年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

The efficacy of programmed cell death-1 (PD-1) blockade in patients with non-small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC-I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC-I expression in NSCLC cell lines. Appropriate EGFR-TKIs increased MHC-I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also increased MHC-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK-ERK pathway mediates the down-regulation of MHC-I expression in response to EGFR activation. Immunohistochemical analysis of EGFR-mutated NSCLC specimens obtained before and after EGFR-TKI treatment also revealed down-regulation of phosphorylated forms of EGFR and ERK in association with up-regulation of MHC-I, an increased number of infiltrating CD8+ T cells, and increased PD-1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC-I expression through the MEK-ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR-MEK-ERK signaling in and the immune response to EGFR-mutated NSCLC. .

DOI： 10.1111/cas.13860

Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. 査読

Togashi Y, Shitara K, Nishikawa H

Nature reviews. Clinical oncology 16 ( 6 ) 356 - 371 2019年1月

非小細胞肺癌において上皮成長因子受容体が変異活性化すると細胞外シグナル調節キナーゼを介して主要組織適合遺伝子複合体クラスIの発現が下方制御される(Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer)

Watanabe Satomi, Hayashi Hidetoshi, Haratani Koji, Shimizu Shigeki, Tanizaki Junko, Sakai Kazuko, Kawakami Hisato, Yonesaka Kimio, Tsurutani Junji, Togashi Yosuke, Nishio Kazuto, Ito Akihiko, Nakagawa Kazuhiko

Cancer Science 110 ( 1 ) 52 - 60 2019年1月

Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8⁺ T cells in the tumor microenvironment. 査読国際誌

Tada Y, Togashi Y, Kotani D, Kuwata T, Sato E, Kawazoe A, Doi T, Wada H, Nishikawa H, Shitara K

Journal for immunotherapy of cancer 6 ( 1 ) 106 - 106 2018年10月

Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein–Barr virus status, and cancer genome alterations in metastatic gastric cancer 査読

Akihito Kawazoe, Kohei Shitara, Yasutoshi Kuboki, Hideaki Bando, Takashi Kojima, Takayuki Yoshino, Atsushi Ohtsu, Atsushi Ochiai, Yosuke Togashi, Hiroyoshi Nishikawa, Toshihiko Doi, Takeshi Kuwata

Gastric Cancer 1 - 8 2018年6月

Immunological impact of ramucirumab on tumor microenvironment in advanced gastric cancer. 査読

Togashi Yosuke, Tada Yasuko, Kotani Daisuke, Kawazoe Akihito, Doi Toshihiko, Nishikawa Hiroyoshi

https://jitc.biomedcentral.com 36 ( 5 ) 2018年2月

Suppression from beyond the grave 査読

Yosuke Togashi, Hiroyoshi Nishikawa

NATURE IMMUNOLOGY 18 ( 12 ) 1285 - 1286 2017年12月

Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment 査読

K. Haratani, H. Hayashi, T. Tanaka, H. Kaneda, Y. Togashi, K. Sakai, K. Hayashi, S. Tomida, Y. Chiba, K. Yonesaka, Y. Nonagase, T. Takahama, J. Tanizaki, K. Tanaka, T. Yoshida, K. Tanimura, M. Takeda, H. Yoshioka, T. Ishida, T. Mitsudomi, K. Nishio, K. Nakagawa

ANNALS OF ONCOLOGY 28 ( 7 ) 1532 - 1539 2017年7月

Clinical significance of Akt2 in advanced pancreatic cancer treated with erlotinib 査読

Eri Banno, Yosuke Togashi, Marco A. De Velasco, Takuro Mizukami, Yu Nakamura, Masato Terashima, Kazuko Sakai, Yoshihiko Fujita, Ken Kamata, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio

INTERNATIONAL JOURNAL OF ONCOLOGY 50 ( 6 ) 2049 - 2058 2017年6月

Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A 査読

Masato Chiba, Yosuke Togashi, Eri Bannno, Yoshihisa Kobayashi, Yu Nakamura, Hidetoshi Hayashi, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

BMC CANCER 17 ( 1 ) 281 2017年4月

Characterization of EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib in Lung Cancer 査読

Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Hak Kim, Yosuke Togashi, Yuichi Sesumi, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi

MOLECULAR CANCER THERAPEUTICS 16 ( 2 ) 357 - 364 2017年2月

Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies 査読国際誌

Takuro Mizukami, Yosuke Togashi, Saeko Naruki, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Azusa Yoneshige, Hidetoshi Hayashi, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Takashi Fujino, Narikazu Boku, Akihiko Ito, Kazuhiko Nakagawa, Kazuto Nishio

Molecular Carcinogenesis 56 ( 1 ) 106 - 117 2017年1月

Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies 査読

Takuro Mizukami, Yosuke Togashi, Saeko Naruki, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Azusa Yoneshige, Hidetoshi Hayashi, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Takashi Fujino, Narikazu Boku, Akihiko Ito, Kazuhiko Nakagawa, Kazuto Nishio

MOLECULAR CARCINOGENESIS 56 ( 1 ) 106 - 117 2017年1月

Regulatory T Cells: Molecular and Cellular Basis for Immunoregulation 査読

Yosuke Togashi, Hiroyoshi Nishikawa

EMERGING CONCEPTS TARGETING IMMUNE CHECKPOINTS IN CANCER AND AUTOIMMUNITY 410 3 - 27 2017年

MEK inhibitors against MET-amplified non-small cell lung cancer 査読

Masato Chiba, Yosuke Togashi, Shuta Tomida, Hiroshi Mizuuchi, Yu Nakamura, Eri Banno, Hidetoshi Hayashi, Masato Terashima, Marco A. De Velasc, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

INTERNATIONAL JOURNAL OF ONCOLOGY 49 ( 6 ) 2236 - 2244 2016年12月

FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib 査読

Masaaki Hibi, Hiroyasu Kaneda, Junko Tanizaki, Kazuko Sakai, Yosuke Togashi, Masato Terashima, Marco Antonio De Velasco, Yoshihiko Fujita, Eri Banno, Yu Nakamura, Masayuki Takeda, Akihiko Ito, Tetsuya Mitsudomi, Kazuhiko Nakagawa, Isamu Okamoto, Kazuto Nishio

CANCER SCIENCE 107 ( 11 ) 1667 - 1676 2016年11月

Case report: Durable response to afatinib in a patient with lung cancer harboring two uncommon mutations of EGFR and a KRAS mutation 査読

Junko Tanizaki, Eri Banno, Yosuke Togashi, Hidetoshi Hayashi, Kazuko Sakai, Masayuki Takeda, Hiroyasu Kaneda, Kazuto Nishio, Kazuhiko Nakagawa

LUNG CANCER 101 11 - 15 2016年11月

Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor? 査読

Eri Banno, Yosuke Togashi, Yu Nakamura, Masato Chiba, Yoshihisa Kobayashi, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

CANCER SCIENCE 107 ( 8 ) 1134 - 1140 2016年8月

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC 査読

Yu Nakamura, Yosuke Togashi, Hirokazu Nakahara, Shuta Tomida, Eri Banno, Masato Terashima, Hidetoshi Hayashi, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Takatsugu Okegawa, Kikuo Nutahara, Suguru Hamada, Kazuto Nishio

MOLECULAR CANCER THERAPEUTICS 15 ( 8 ) 1988 - 1997 2016年8月

Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non-Small Cell Lung Cancer: Double-Edged Sword of DDR2 査読

Masato Terashima, Yosuke Togashi, Katsuaki Sato, Hiroshi Mizuuchi, Kazuko Sakai, Kenichi Suda, Yu Nakamura, Eri Banno, Hidetoshi Hayashi, Marco A. De Velasco, Yoshihiko Fujita, Shuta Tomida, Tetsuya Mitsudomi, Kazuto Nishio

CLINICAL CANCER RESEARCH 22 ( 14 ) 3663 - 3671 2016年7月

EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs 査読

Yoshihisa Kobayashi, Yosuke Togashi, Yasushi Yatabe, Hiroshi Mizuuchi, Park Jangchul, Chiaki Kondo, Masaki Shimoji, Katsuaki Sato, Kenichi Suda, Kenji Tomizawa, Toshiki Takemoto, Toyoaki Hida, Kazuto Nishio, Tetsuya Mitsudomi

CLINICAL CANCER RESEARCH 21 ( 23 ) 5305 - 5313 2015年12月

MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor 査読

Yosuke Togashi, Hiroshi Mizuuchi, Shuta Tomida, Masato Terashima, Hidetoshi Hayashi, Kazuto Nishio, Tetsuya Mitsudomi

LUNG CANCER 90 ( 3 ) 590 - 597 2015年12月

Clinicopathological and Genetic Differences Between Low-Grade and High-Grade Colorectal Mucinous Adenocarcinomas 査読

Yasumasa Yoshioka, Yosuke Togashi, Takaaki Chikugo, Akihiro Kogita, Masataka Taguri, Masato Terashima, Takuro Mizukami, Hidetoshi Hayashi, Kazuko Sakai, Marco A. de Velasco, Shuta Tomida, Yoshihiko Fujita, Tadao Tokoro, Akihiko Ito, Kiyotaka Okuno, Kazuto Nishio

CANCER 121 ( 24 ) 4359 - 4368 2015年12月

Urinary kidney injury molecule-1 and monocyte chemotactic protein-1 are noninvasive biomarkers of cisplatin-induced nephrotoxicity in lung cancer patients 査読

Haruka Shinke, Satohiro Masuda, Yousuke Togashi, Yasuaki Ikemi, Aiko Ozawa, Tomoko Sato, Young Hak Kim, Michiaki Mishima, Takaharu Ichimura, Joseph V. Bonventre, Kazuo Matsubara

CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 ( 5 ) 989 - 996 2015年11月

An activating ALK gene mutation in ALK IHC-positive/FISH-negative nonsmall-cell lung cancer 査読

Y. Togashi, H. Mizuuchi, Y. Kobayashi, H. Hayashi, M. Terashima, K. Sakai, E. Banno, T. Mizukami, Y. Nakamura, M. A. de Velasco, Y. Fujita, S. Tomida, T. Mitsudomi, K. Nishio

ANNALS OF ONCOLOGY 26 ( 8 ) 1800 - 1801 2015年8月

EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition 査読

Takuro Mizukami, Yosuke Togashi, Shunsuke Sogabe, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Kazuto Nishio

INTERNATIONAL JOURNAL OF ONCOLOGY 47 ( 2 ) 499 - 505 2015年8月

[Kinase inhibitors and their resistance]. 査読

Togashi Y, Nishio K

Nihon rinsho. Japanese journal of clinical medicine 73 ( 8 ) 1323 - 1329 2015年8月

[PI3K and mTOR pathway and molecular targeted agents]. 査読

Nishio K, Sakai K, Togashi Y

Nihon rinsho. Japanese journal of clinical medicine 73 ( 8 ) 1315 - 1322 2015年8月

Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study 査読

Hiroki Yamaue, Takuya Tsunoda, Masaji Tani, Motoki Miyazawa, Kenji Yamao, Nobumasa Mizuno, Takuji Okusaka, Hideki Ueno, Narikazu Boku, Akira Fukutomi, Hiroshi Ishii, Shinichi Ohkawa, Masayuki Furukawa, Hiroyuki Maguchi, Masafumi Ikeda, Yosuke Togashi, Kazuto Nishio, Yasuo Ohashi

CANCER SCIENCE 106 ( 7 ) 883 - 890 2015年7月

Extended RAS and BRAF Mutation Analysis Using Next-Generation Sequencing 査読

Kazuko Sakai, Junji Tsurutani, Takeharu Yamanaka, Azusa Yoneshige, Akihiko Ito, Yosuke Togashi, Marco A. De Velasco, Masato Terashima, Yoshihiko Fujita, Shuta Tomida, Takao Tamura, Kazuhiko Nakagawa, Kazuto Nishio

PLOS ONE 10 ( 5 ) e0121891 2015年5月

Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal 査読

Yosuke Togashi, Hidetoshi Hayashi, Kunio Okamoto, Soichi Fumita, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Kazuhiko Nakagawa, Kazuto Nishio

LUNG CANCER 88 ( 1 ) 16 - 23 2015年4月

Afatinib is Especially Effective Against Non-small Cell Lung Cancer Carrying an EGFR Exon 19 Deletion 査読

Eri Banno, Yosuke Togashi, Yoshihisa Kobayashi, Hidetoshi Hayashi, Tetsuya Mitsudomi, Kazuto Nishio

ANTICANCER RESEARCH 35 ( 4 ) 2005 - 2008 2015年4月

Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer 査読

Akihiro Kogita, Yosuke Togashi, Hidetoshi Hayashi, Eri Banno, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Yoshifumi Takeyama, Kiyotaka Okuno, Kazuhiko Nakagawa, Kazuto Nishio

INTERNATIONAL JOURNAL OF ONCOLOGY 46 ( 3 ) 1025 - 1030 2015年3月

Inter- and intra-tumor profiling of multi-regional colon cancer and metastasis 査読

Akihiro Kogita, Yasumasa Yoshioka, Kazuko Sakai, Yosuke Togashi, Shunsuke Sogabe, Takuya Nakai, Kiyotaka Okuno, Kazuto Nishio

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 458 ( 1 ) 52 - 56 2015年2月

Impact of Pretreatment Interstitial Lung Disease on Radiation Pneumonitis and Survival after Stereotactic Body Radiation Therapy for Lung Cancer 査読

Nami Ueki, Yukinori Matsuo, Yosuke Togashi, Takeshi Kubo, Keiko Shibuya, Yusuke Iizuka, Takashi Mizowaki, Kaori Togashi, Michiaki Mishima, Masahiro Hiraoka

JOURNAL OF THORACIC ONCOLOGY 10 ( 1 ) 116 - 125 2015年1月

The OCT4 pseudogene POU5F1B is amplified and promotes an aggressive phenotype in gastric cancer 査読

H. Hayashi, T. Arao, Y. Togashi, H. Kato, Y. Fujita, M. A. De Velasco, H. Kimura, K. Matsumoto, K. Tanaka, I. Okamoto, A. Ito, Y. Yamada, K. Nakagawa, K. Nishio

ONCOGENE 34 ( 2 ) 199 - 208 2015年1月

Performance of a novel KRAS mutation assay for formalin-fixed paraffin embedded tissues of colorectal cancer 査読

Kazuko Sakai, Azusa Yoneshige, Akihiko Ito, Yoji Ueda, Satoshi Kondo, Hitoshi Nobumasa, Yoshihiko Fujita, Yosuke Togashi, Masato Terashima, Marco A. De Velasco, Shuta Tomida, Kazuto Nishio

SPRINGERPLUS 4 7 2015年1月

Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer 査読

Yosuke Togashi, Akihiro Kogita, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Masayuki Kitano, Kiyotaka Okuno, Masatoshi Kudo, Kazuto Nishio

CANCER LETTERS 356 ( 2 ) 819 - 827 2015年1月

Inhibition of β-Catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small-cell lung cancer with a T790M mutation. 査読

Togashi Y, Hayashi H, Terashima M, de Velasco MA, Sakai K, Fujita Y, Tomida S, Nakagawa K, Nishio K

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 10 ( 1 ) 93 - 101 2015年1月

Multiple Primary Malignancies in Patients with Non-Small Cell Lung Cancer 査読

Shiro Fujita, Katsuhiro Masago, Jumpei Takeshita, Yosuke Togashi, Akito Hata, Reiko Kaji, Masaki Kokubo, Nobuyuki Katakami

INTERNAL MEDICINE 54 ( 3 ) 325 - 331 2015年

MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations 査読

Shunsuke Sogabe, Yosuke Togashi, Hiroaki Kato, Akihiro Kogita, Takuro Mizukami, Yoichi Sakamoto, Eri Banno, Masato Terashima, Hidetoshi Hayashi, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takushi Yasuda, Yoshifumi Takeyama, Kiyotaka Okuno, Kazuto Nishio

MOLECULAR CANCER THERAPEUTICS 13 ( 12 ) 3098 - 3106 2014年12月

Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition 査読

Akihiro Kogita, Yosuke Togashi, Hidetoshi Hayashi, Shunsuke Sogabe, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Yoshifumi Takeyama, Kiyotaka Okuno, Kazuhiko Nakagawa, Kazuto Nishio

INTERNATIONAL JOURNAL OF ONCOLOGY 45 ( 4 ) 1430 - 1436 2014年10月

KIAA1199 interacts with glycogen phosphorylase kinase β-subunit (PHKB) to promote glycogen breakdown and cancer cell survival. 査読

Terashima M, Fujita Y, Togashi Y, Sakai K, De Velasco MA, Tomida S, Nishio K

Oncotarget 5 ( 16 ) 7040 - 7050 2014年8月

Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines 査読

Masato Terashima, Kazuko Sakai, Yosuke Togashi, Hidetoshi Hayashi, Marco A. De Velasco, Junji Tsurutani, Kazuto Nishio

SPRINGERPLUS 3 417 2014年8月

Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production 査読

Yosuke Togashi, Tokuzo Arao, Hiroaki Kato, Kazuko Matsumoto, Masato Terashima, Hidetoshi Hayashi, Marco A. de Velasco, Yoshihiko Fujita, Hideharu Kimura, Takushi Yasuda, Hitoshi Shiozaki, Kazuto Nishio

ONCOTARGET 5 ( 10 ) 2962 - 2973 2014年5月

Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer 査読

Yosuke Togashi, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Yoshihiko Fujita, Yasuo Kodera, Kazuko Sakai, Shuta Tomida, Masayuki Kitano, Akihiko Ito, Masatoshi Kudo, Kazuto Nishio

MOLECULAR CANCER 13 126 2014年5月

Biomarkers of reactive resistance and early disease progression during chemotherapy plus bevacizumab treatment for colorectal carcinoma 査読

Hidetoshi Hayashi, Tokuzo Arao, Kazuko Matsumoto, Hideharu Kimura, Yosuke Togashi, Yoshinori Hirashima, Yosuke Horita, Satoru Iwasa, Natsuko Tsuda Okita, Yoshitaka Honma, Atsuo Takashima, Ken Kato, Tetsuya Hamaguchi, Yasuhiro Shimada, Kazuhiko Nakagawa, Kazuto Nishio, Yasuhide Yamada

ONCOTARGET 5 ( 9 ) 2588 - 2595 2014年5月

Melanoma Transition Is Frequently Accompanied by a Loss of Cytoglobin Expression in Melanocytes: A Novel Expression Site of Cytoglobin 査読

Yoshihiko Fujita, Satoshi Koinuma, Marco A. De Velasco, Jan Bolz, Yosuke Togashi, Masato Terashima, Hidetoshi Hayashi, Takuya Matsuo, Kazuto Nishio

PLOS ONE 9 ( 4 ) e94772 2014年4月

Clinical utility of erlotinib for the treatment of non-small-cell lung cancer in Japanese patients: current evidence 査読

Yosuke Togashi, Hidetoshi Hayashi, Kazuhiko Nakagawa, Kazuto Nishio

DRUG DESIGN DEVELOPMENT AND THERAPY 8 1037 - 1046 2014年

Population Pharmacokinetics/Pharmacodynamics of Erlotinib and Pharmacogenomic Analysis of Plasma and Cerebrospinal Fluid Drug Concentrations in Japanese Patients with Non-Small Cell Lung Cancer 査読

Masahide Fukudo, Yasuaki Ikemi, Yosuke Togashi, Katsuhiro Masago, Young Hak Kim, Tadashi Mio, Tomohiro Terada, Satoshi Teramukai, Michiaki Mishima, Ken-ichi Inui, Toshiya Katsura

CLINICAL PHARMACOKINETICS 52 ( 7 ) 593 - 609 2013年7月

Continuous morphine infusion for end-stage lung cancer patients 査読

Young Hak Kim, Chiyuki Okuda, Yuichi Sakamori, Katsuhiro Masago, Yosuke Togashi, Michiaki Mishima

ONCOLOGY LETTERS 5 ( 3 ) 972 - 974 2013年3月

Pneumocystis jiroveci pneumonia and colonization in patients with advanced lung cancer. 査読国際誌

Yosuke Togashi, Katsuhiro Masago, Yutaka Ito, Yuichi Sakamori, Chiyuki Okuda, Akiko Fukuhara, Hiroki Nagai, Young Hak Kim, Michiaki Mishima

Oncology letters 5 ( 2 ) 601 - 604 2013年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pneumocystis jiroveci pneumonia (PCP) has long been recognized as a cause of mortality in immuno-compromised populations, including those with advanced lung cancer. Although Pneumocystis colonization has only recently been described due to the development of more sensitive molecular techniques, including polymerase chain reaction (PCR), it is unknown whether Pneumocystis colonization leads to the development of PCP. In the present study, we aimed to determine the prevalence of Pneumocystis colonization in advanced lung cancer patients. Furthermore, the association between PCP and Pneumocystis colonization was also investigated. Advanced lung cancer patients with no indication of PCP were evaluated to determine the prevalence of Pneumocystis colonization. We analyzed their oral wash (OW) samples and retrospectively evaluated advanced lung cancer patients with PCP by analyzing their sections of formalin-fixed, paraffin-embedded lung tissues obtained following a diagnosis of lung cancer. Pneumocystis colonization was determined by a PCR test for Pneumocystis jiroveci (P. jiroveci). No P. jiroveci was detected by PCR in the OW samples of 47 advanced lung cancer patients with no indication of PCP, or in the lung tissues of four advanced lung cancer patients with PCP. These results indicate that PCP is not associated with Pneumocystis colonization in advanced lung cancer patients, although this study is limited since this was a cross-sectional and retrospective study.

DOI： 10.3892/ol.2012.1052

Effect of the BCL2 gene polymorphism on survival in advanced-stage non-small cell lung cancer patients who received chemotherapy. 査読国際誌

Katsuhiro Masago, Yosuke Togashi, Shiro Fujita, Hiroki Nagai, Yuichi Sakamori, Chiyuki Okuda, Young Hak Kim, Michiaki Mishima

Oncology 84 ( 4 ) 214 - 8 2013年

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: This study aimed to evaluate the association between BCL2 single-nucleotide polymorphisms and survival outcome in advanced non-small cell lung cancer (NSCLC). METHODS: One hundred and sixty-eight patients with advanced NSCLC who were treated with anti-cancer drugs and could be evaluated for therapeutic response between April 2005 and March 2010 at Kyoto University Hospital were enrolled. DNA was extracted from peripheral blood samples. The BCL2 polymorphisms -938 C→A (rs2279115) and +21 A→G (rs1801018) were genotyped using the 5'-nuclease assay. The univariate relationship between each independent clinicopathologic variable and BCL2 genotype was examined using Fisher's exact test. To evaluate risk factors associated with prognosis, a Cox proportional hazards regression model with a step-down procedure was used. RESULTS: The median survival time of patients with the -938 AA and AC genotypes were significantly shorter than those with the -938 CC genotype (p = 0.027 by log-rank test). Based on multivariate analysis, poor performance status [hazard ratio (HR) 2.424, 95% confidence interval (CI) 1.727-3.262; p < 0.0001], non-adenocarcinoma histology (HR 1.512, 95% CI 1.167-1.938; p = 0.0048) and the BCL2 -938 AA + AC genotype (HR 1.219, 95% CI, 1.024-1.456; p = 0.0256) were significant independent prognostic factors for survival. CONCLUSIONS: Polymorphisms in BCL2 may be associated with survival in advanced-stage NSCLC patients who received chemotherapy.

DOI： 10.1159/000342854

Association between vascular-poor area of primary tumors and epidermal growth factor receptor gene status in advanced lung adenocarcinoma 査読

Yosuke Togashi, Katsuhiro Masago, Takeshi Kubo, Daichi Fujimoto, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Kaori Togashi, Michiaki Mishima

MEDICAL ONCOLOGY 29 ( 5 ) 3169 - 3175 2012年12月

Clinical significance of serum hepatocyte growth factor and epidermal growth factor gene somatic mutations in patients with non-squamous non-small cell lung cancer receiving gefitinib or erlotinib 査読

Katsuhiro Masago, Yosuke Togashi, Shiro Fujita, Yuichi Sakamori, Chiyuki Okuda, Young Hak Kim, Tadashi Mio, Michiaki Mishima

MEDICAL ONCOLOGY 29 ( 3 ) 1614 - 1621 2012年9月

Expressions of Insulin-Like Growth Factor Receptor-1 and Insulin-Like Growth Factor Binding Protein 3 in Advanced Non-Small-Cell Lung Cancer 査読

Young Hak Kim, Shinji Sumiyoshi, Seiji Hashimoto, Katsuhiro Masago, Yosuke Togashi, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

CLINICAL LUNG CANCER 13 ( 5 ) 385 - 390 2012年9月

Coronary Air Embolism and Cardiogenic Shock During Computed Tomography-Guided Needle Biopsy of the Lung 査読

Tetsuma Kawaji, Hiroki Shiomi, Yosuke Togashi, Daigo Gunji, Masao Imai, Takahiro Doi, Takeshi Kimura

CIRCULATION 126 ( 13 ) E195 - E197 2012年9月

Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer 査読

Yosuke Togashi, Katsuhiro Masago, Satohiro Masuda, Tomoyuki Mizuno, Masahide Fukudo, Yasuaki Ikemi, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Toshiya Katsura, Michiaki Mishima

CANCER CHEMOTHERAPY AND PHARMACOLOGY 70 ( 3 ) 399 - 405 2012年9月

Phase II study of carboplatin and pemetrexed in advanced non-squamous, non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0902 査読

Young Hak Kim, Masataka Hirabayashi, Yosuke Togashi, Katsuya Hirano, Keisuke Tomii, Katsuhiro Masago, Toshihiko Kaneda, Harukazu Yoshimatsu, Koujirou Otsuka, Tadashi Mio, Hiromi Tomioka, Yujiro Suzuki, Michiaki Mishima

CANCER CHEMOTHERAPY AND PHARMACOLOGY 70 ( 2 ) 271 - 276 2012年8月

Successful erlotinib rechallenge for leptomeningeal metastases of lung adenocarcinoma after erlotinib-induced interstitial lung disease: A case report and review of the literature 査読

Yosuke Togashi, Katsuhiro Masago, Yasuhiro Hamatani, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Michiaki Mishima

LUNG CANCER 77 ( 2 ) 464 - 468 2012年8月

Prognostic Significance of Preexisting Interstitial Lung Disease in Japanese Patients With Small-Cell Lung Cancer 査読

Yosuke Togashi, Katsuhiro Masago, Tomohiro Handa, Kiminobu Tanizawa, Chiyuki Okuda, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Michiaki Mishima

CLINICAL LUNG CANCER 13 ( 4 ) 304 - 311 2012年7月

Nitric oxide (NO) enhances pemetrexed cytotoxicity via NO‑cGMP signaling in lung adenocarcinoma cells in vitro and in vivo. 査読

Nagai H, Yasuda H, Hatachi Y, Xue D, Sasaki T, Yamaya M, Sakamori Y, Togashi Y, Masago K, Ito I, Kim YH, Mio T, Mishima M

International journal of oncology 41 ( 1 ) 24 - 30 2012年7月

Increase in circulating endothelial progenitor cells predicts response in patients with advanced non-small-cell lung cancer 査読

Yuichi Sakamori, Katsuhiro Masago, Katsuyuki Ohmori, Yosuke Togashi, Hiroki Nagai, Chiyuki Okuda, Young Hak Kim, Satoshi Ichiyama, Michiaki Mishima

CANCER SCIENCE 103 ( 6 ) 1065 - 1070 2012年6月

Significance of pretreatment comorbidities in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitor 査読

Kaoru Irisa, Katsuhiro Masago, Yosuke Togashi, Shiro Fujita, Yukimasa Hatachi, Akiko Fukuhara, Yuichi Sakamori, Yung Hak Kim, Tadashi Mio, Michiaki Mishima

MEDICAL ONCOLOGY 29 ( 1 ) 185 - 192 2012年3月

Clinical significance of epidermal growth factor receptor mutations and insulin-like growth factor 1 and its binding protein 3 in advanced non-squamous non-small cell lung cancer 査読

Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Kaoru Irisa, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

ONCOLOGY REPORTS 26 ( 4 ) 795 - 803 2011年10月

Differences in adverse events between 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer 査読

Yosuke Togashi, Katsuhiro Masago, Shiro Fujita, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Yuichi Sakamori, Young Hak Kim, Tadashi Mio, Michiaki Mishima

LUNG CANCER 74 ( 1 ) 98 - 102 2011年10月

Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation 査読

Yosuke Togashi, Katsuhiro Masago, Masahide Fukudo, Yasuhiro Tsuchido, Chiyuki Okuda, Young Hak Kim, Yasuaki Ikemi, Yuichi Sakamori, Tadashi Mio, Toshiya Katsura, Michiaki Mishima

CANCER CHEMOTHERAPY AND PHARMACOLOGY 68 ( 4 ) 1089 - 1092 2011年10月

Plasma and Pleural Fluid Pharmacokinetics of Erlotinib and its Active Metabolite OSI-420 in Patients With Non-Small-Cell Lung Cancer With Pleural Effusion 査読

Katsuhiro Masago, Yosuke Togashi, Masahide Fukudo, Tomohiro Terada, Kaoru Irisa, Yuichi Sakamori, Young Hak Kim, Tadashi Mio, Ken-ichi Inui, Michiaki Mishima

CLINICAL LUNG CANCER 12 ( 5 ) 307 - 312 2011年9月

Pulmonary embolism due to internal jugular vein thrombosis in a patient with non-small cell lung cancer receiving bevacizumab 査読

Yosuke Togashi, Young Hak Kim, Katsuhiro Masago, Koji Tamai, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 16 ( 4 ) 444 - 446 2011年8月

Good Clinical Response to Erlotinib in a Patient With Anaplastic Thyroid Carcinoma Harboring an Epidermal Growth Factor Somatic Mutation, L858R, in Exon 21 査読

Katsuhiro Masago, Masako Miura, Yoshiro Toyama, Yosuke Togashi, Michiaki Mishima

JOURNAL OF CLINICAL ONCOLOGY 29 ( 16 ) E465 - E467 2011年6月

Two Cases of Cancer-associated Retinopathy Combined with Small-cell Lung Cancer 査読

Yuichi Sakamori, Young Hak Kim, Chiyuki Okuda, Yosuke Togashi, Daisuke Kinose, Katsuhiro Masago, Tadashi Mio, Akihito Uji, Michiaki Mishima

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 ( 5 ) 669 - 673 2011年5月

Long-term Survival in a Patient with Small-cell Lung Cancer Undergoing Hemodialysis Who Received Multiple Courses of Chemotherapy 査読

Yosuke Togashi, Young Hak Kim, Katsuhiro Masago, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 ( 4 ) 582 - 585 2011年4月

EGFR mutation: Significance as a stratification factor in the era of molecular-targeted therapy 査読

Young Hak Kim, Katsuhiro Masago, Yosuke Togashi, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

ONCOLOGY LETTERS 2 ( 2 ) 383 - 387 2011年3月

Association between brain natriuretic peptide and distant metastases in advanced non-small cell lung cancer patients 査読

Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Kaoru Irisa, Yuichi Sakamori, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Young Hak Kim, Tadashi Mio, Michiaki Mishima

ONCOLOGY LETTERS 2 ( 2 ) 253 - 256 2011年3月

Successful Treatment with Pemetrexed in a Patient with Mucinous Bronchioloalveolar Carcinoma Long-Term Response Duration with Mild Toxicity 査読

Chiyuki Okuda, Young Hak Kim, Kengo Takeuchi, Yosuke Togashi, Katsuhiro Masago, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

JOURNAL OF THORACIC ONCOLOGY 6 ( 3 ) 641 - 642 2011年3月

Clinical significance of the ratio between the alpha 2 plasmin inhibitor-plasmin complex and the thrombin-antithrombin complex in advanced non-small cell lung cancer 査読

Katsuhiro Masago, Shiro Fujita, Tadashi Mio, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Kaoru Irisa, Yuichi Sakamori, Michiaki Mishima

MEDICAL ONCOLOGY 28 ( 1 ) 351 - 356 2011年3月

Phase I study of the combination of nedaplatin and gemcitabine in previously untreated advanced squamous cell lung cancer 査読

Katsuhiro Masago, Shiro Fujita, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Kaoru Irisa, Hiroki Nagai, Yuichi Sakamori, Yosuke Togashi, Tadashi Mio, Michiaki Mishima

CANCER CHEMOTHERAPY AND PHARMACOLOGY 67 ( 2 ) 325 - 330 2011年2月

Association of the transforming growth factor ß1 promoter polymorphism, C-509T, with smoking status and survival in advanced non-small cell lung cancer. 査読

Togashi Y, Masago K, Fujita S, Kim YH, Sakamori Y, Hatachi Y, Fukuhara A, Nagai H, Mio T, Mishima M

Oncology reports 25 ( 2 ) 377 - 382 2011年2月

Association of Diffuse, Random Pulmonary Metastases, Including Miliary Metastases, With Epidermal Growth Factor Receptor Mutations in Lung Adenocarcinoma 査読

Yosuke Togashi, Katsuhiro Masago, Takeshi Kubo, Yuichi Sakamori, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Tadashi Mio, Kaori Togashi, Michiaki Mishima

CANCER 117 ( 4 ) 819 - 825 2011年2月

Clinicopathologic Factors Affecting the Progression-Free Survival of Patients With Advanced Non-Small-Cell Lung Cancer After Gefitinib Therapy 査読

Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

CLINICAL LUNG CANCER 12 ( 1 ) 56 - 61 2011年1月

Octreotide, a Somatostatin Analogue, in the Treatment of Chylothorax Associated with Idiopathic Fibrosing Mediastinitis 査読

Yosuke Togashi, Young Hak Kim, Ryo Miyahara, Kaoru Irisa, Yuichi Sakamori, Katsuhiro Masago, Tadashi Mio, Hiroshi Date, Michiaki Mishima

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 222 ( 1 ) 51 - 53 2010年9月

Infectious background of febrile advanced lung cancer patients who received chemotherapy 査読

Katsuhiro Masago, Akiko Fukuhara, Yutaka Ito, Yukimasa Hatachi, Kaoru Irisa, Yuichi Sakamori, Yosuke Togashi, Shiro Fujita, Young Hak Kim, Tadashi Mio, Michiaki Mishima

ONCOLOGY LETTERS 1 ( 5 ) 849 - 853 2010年9月

Cerebrospinal Fluid Concentration of Erlotinib and its Active Metabolite OSI-420 in Patients with Central Nervous System Metastases of Non-small Cell Lung Cancer 査読

Yosuke Togashi, Katsuhiro Masago, Masahide Fukudo, Tomohiro Terada, Shiro Fujita, Kaoru Irisa, Yuichi Sakamori, Young Hak Kim, Tadashi Mio, Ken-ichi Inui, Michiaki Mishima

JOURNAL OF THORACIC ONCOLOGY 5 ( 7 ) 950 - 955 2010年7月

A Case of Radiation Recall Pneumonitis Induced by Erlotinib, Which Can be Related to High Plasma Concentration 査読

Yosuke Togashi, Katsuhiro Masago, Michiaki Mishima, Masahide Fukudo, Ken-ichi Inui

JOURNAL OF THORACIC ONCOLOGY 5 ( 6 ) 924 - 925 2010年6月

Pharmacokinetics of Erlotinib and Its Active Metabolite OSI-420 in Patients with Non-small Cell Lung Cancer and Chronic Renal Failure Who Are Undergoing Hemodialysis 査読

Yosuke Togashi, Katsuhiro Masago, Masahide Fukudo, Tomohiro Terada, Yasuaki Ikemi, Young Hak Kim, Shiro Fujita, Kaoru Irisa, Yuichi Sakamori, Tadashi Mio, Ken-ichi Inui, Michiaki Mishima

JOURNAL OF THORACIC ONCOLOGY 5 ( 5 ) 601 - 605 2010年5月

Good Clinical Response to Erlotinib in a Non-Small Cell Lung Cancer Patient Harboring Multiple Brain Metastases and a Double Active Somatic Epidermal Growth Factor Gene Mutation. 査読国際誌

Katsuhiro Masago, Yosuke Togashi, Masahide Fukudo, Tomohiro Terada, Kaoru Irisa, Yuichi Sakamori, Shiro Fujita, Young Hak Kim, Tadashi Mio, Ken-Ichi Inui, Michiaki Mishima

Case reports in oncology 3 ( 2 ) 98 - 105 2010年4月

記述言語：英語

Recently, 2 small molecule kinase inhibitors (TKIs), targeting epidermal growth factor receptor (EGFR), have proven effective in the treatment of non-small cell lung cancer. However, it is unknown whether the EGFR double activating mutation of L858R in exon 21 and the in-frame deletion in exon 19 is a predictor of the effectiveness of EGFR-TKIs. We report for the first time a case of non-small cell lung cancer with central nervous system metastases harboring a rare EGFR double activating mutation who showed a good clinical response to erlotinib, regardless of his poor performance status, as swallowing is not possible. Therefore, we suggest that erlotinib may become a therapeutic choice in cases of central nervous system metastases even with poor performance status.

DOI： 10.1159/000310830

Outcome of Surgical Treatment for Metastatic Vertebra Bone Tumor in Advanced Lung Cancer. 査読国際誌

Akiko Fukuhara, Katsuhiro Masago, Masashi Neo, Shunsuke Fujibayashi, Shiro Fujita, Yukimasa Hatachi, Kaoru Irisa, Yuichi Sakamori, Yosuke Togashi, Young Hak Kim, Tadashi Mio, Michiaki Mishima

Case reports in oncology 3 ( 1 ) 63 - 71 2010年3月

記述言語：英語

BACKGROUND: Spinal metastases of patients with advanced stage lung cancer are an important target for palliative therapy, because their incidence is high, and they often cause severe symptoms and worsen the quality of life. Surgery is one of the most effective treatment options, but the indication of surgery is unclear as the procedure is invasive and patients with spinal metastasis have a rather short life expectancy. Furthermore, there have been few studies that have focused on lung cancer with poor prognosis. METHODS: We reviewed all of the cases of lung cancer from January 1999 to July 2007 in the Department of Respiratory Medicine, Kyoto University Hospital, Japan. Thirteen patients with metastatic spinal tumor of lung cancer underwent surgery, and all of them had a poor performance status score (3 or 4). RESULTS: Neurological improvement by at least 1 Frankel grade was seen in 10 of 14 cases (71%). Improvement of the movement capacity was noted in 9 of 14 cases (64%), and pain improvement was noted in 12 of 14 (86%). Median postoperative survival was 5 months (1-25 months). In particular, the group with a good postoperative performance status score (0-2) was shown to have a better median postoperative survival of 13 months. CONCLUSIONS: Surgical treatment for symptomatic metastatic spinal tumor of lung cancer can improve quality of life in a substantially high percentage of patients. Surgery should be considered even if preoperative performance status is poor.

DOI： 10.1159/000299385

Clinical Significance of Pretreatment C-Reactive Protein in Patients with Advanced Nonsquamous, Non-Small Cell Lung Cancer Who Received Gefitinib 査読

Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Kaoru Irisa, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

ONCOLOGY 79 ( 5-6 ) 355 - 362 2010年

急性骨髄性白血病を発症したLoeys-Dietz症候群査読

冨樫庸介, 迫田寛人, 菅原浩之, 浅越康助, 松澤佑次

臨床血液 49 ( 8 ) 664 - 667 2008年8月

大動脈瘤に起因する慢性播種性血管内凝固症候群を呈した家族性高コレステロール血症の1例

冨樫庸介, 菅原浩之, 平岡久豊, 松澤佑次

住友病院医学雑誌 ( 35 ) 45 - 50 2008年7月

A Japanese family of typical loeys-dietz syndrome with a TGFBR2 mutation 査読

Yosuke Togashi, Hiroto Sakoda, Akira Nishimura, Naomichi Matsumoto, Hisatoyo Hiraoka, Yuji Matsuzawa

INTERNAL MEDICINE 46 ( 24 ) 1995 - 2000 2007年

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