研究者詳細 - 冨樫　庸介

論文 - 冨樫　庸介

分割表示 155 件中 1 - 20 件目／全件表示 >>

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

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