Faculty Profiles - Togashi Yosuke

Papers - Togashi Yosuke

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Combination therapy with hydrogen peroxide and irradiation promotes an abscopal effect in mouse models. Reviewed International journal

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

Cancer science 114 ( 10 ) 3848 - 3856 2023.7

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

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

Cancer immunology research 11 ( 7 ) OF1-OF14 - 908 2023.4

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

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

Cancer science 114 ( 5 ) 1859 - 1870 2023.2

Authorship：Last author,　Corresponding author Language：English Publisher：(一社)日本癌学会

Combination therapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4+ T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA-4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg cell-mediated immunosuppressive functions, suppressing antigen-presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti-CTLA-4 mAb with antibody-dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that only CTLA-4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg-cell proliferation in mouse models. CTLA-4 blockade also augmented CTLA-4-independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor-infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg-cell depletion to achieve tumor regression in response to CTLA-4 blockade therapies.

DOI： 10.1111/cas.15756

Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite deriving neoantigens. Reviewed International journal

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 2023.2

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. Invited International journal

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

Frontiers in oncology 13 1240926 - 1240926 2023

Tumor-promoting function and regulatory landscape of PD-L2 in B-cell lymphoma. Reviewed International journal

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 2022.12

Resistance to immune checkpoint inhibitors and the tumor microenvironment. Invited Reviewed International journal

Shusuke Kawashima, Yosuke Togashi

Experimental dermatology 2022.11

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. Invited Reviewed International journal

Joji Nagasaki, Yosuke Togashi

International immunology 34 ( 11 ) 563 - 570 2022.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. Invited Reviewed International journal

Joji Nagasaki, Takamasa Ishino, Yosuke Togashi

Cancer science 113 ( 10 ) 3303 - 3312 2022.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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 Reviewed

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 2022.7

Authorship：Last author,　Corresponding author Publishing type：Research paper (scientific journal) Publisher：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. Reviewed International journal

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 2022.2

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

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 2022.1

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

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 2022.1

Language：English Publishing type：Research paper (scientific journal)

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. Invited Reviewed International journal

Hiromasa Yamamoto, Yosuke Togashi

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 17 ( 1 ) 10 - 12 2022.1

Transcript-targeted analysis reveals isoform alterations and double-hop fusions in breast cancer. Reviewed International journal

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 2021.11

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

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 2021.11

TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment. Reviewed International journal

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 ) 2021.11

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

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 2021.10

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

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 2021.9

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

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 ) 2021.5

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

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

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