体細胞変異に伴う抗腫瘍免疫応答に対する新たな免疫編集機構の解析

2020 Fiscal Year Annual Research Report

• Project/Area Number: 19K22574
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: 冨樫 庸介 千葉県がんセンター(研究所), がん治療開発グループ 細胞治療開発研究部, 部長代理 (80758326)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: 腫瘍免疫 / がん免疫編集 / ネオ抗原

Outline of Annual Research Achievements

前年度の非小細胞肺癌、大腸癌に加えてMSI-Hという異常に体細胞変異が多いタイプの大腸癌の臨床検体を用いて解析を行った。免疫染色や遺伝子発現解析からはMSI-H大腸癌では必ずしも全例で免疫応答が強く起きているわけではなく、ゲノム解析からはHLAの変異や脱落により免疫応答が落ちているパターンが見られた。またHLAに異常がない集団でも、ネオ抗原が多いにも拘わらず、免疫応答が低下している患者群が見られた。特にMSI-Hで過去にも報告がある共通のネオ抗原を有しているものの、免疫応答があまり起きていような患者群も存在した。そこで遺伝子発現解析から、これらの免疫応答が起きていない集団で上がっている免疫抑制に関わるシグナルを同定した。そして、このシグナル自体がネオ抗原に関連する可能性をin vitroで証明した。さらにこのシグナルに関わる遺伝子を強制発現もしくはノックダウンしたマウス腫瘍細胞株を複数作成し、in vivoの検証を行ったところ、そのようなシグナルが抗腫瘍免疫応答を抑制し、抗PD-1抗体治療の耐性に関わることが明らかになった。
以上より、体細胞変異・ネオ抗原に対する抗腫瘍免疫応答を腫瘍側の悪性化に関わるシグナルが抑制するような新たな免疫編集機構の存在が複数の癌で明らかにされ、単純なネオ抗原という量的な評価だけでは限界で、より質的な評価が必要であることが示唆された。

Research Products

• [Journal Article] Aging, cancer, and antitumor immunity (2021)
  • Author(s): Ikeda Hideki、Togashi Yosuke
  • Journal Title: International Journal of Clinical Oncology Volume: Epub Pages: Epub
  • DOI: 10.1007/s10147-021-01913-z
  • Peer Reviewed
• [Journal Article] Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer (2021)
  • Author(s): Inamori Koji、Togashi Yosuke、Fukuoka Shota、Akagi Kiwamu、Ogasawara Kouetsu、Irie Takuma、Motooka Daisuke、Kobayashi Yoichi、Sugiyama Daisuke、Kojima Motohiro、Shiiya Norihiko、Nakamura Shota、Maruyama Shoichi、Suzuki Yutaka、Ito Masaaki、Nishikawa Hiroyoshi
  • Journal Title: JCI Insight Volume: 6 Pages: 137365
  • DOI: 10.1172/jci.insight.137365
  • Peer Reviewed / Open Access
• [Journal Article] HSP90 inhibition overcomes EGFR amplification‐induced resistance to third‐generation EGFR‐TKIs (2021)
  • Author(s): Watanabe Sho、Goto Yasushi、Yasuda Hiroyuki、Kohno Takashi、Motoi Noriko、Ohe Yuichiro、Nishikawa Hiroyoshi、Kobayashi Susumu S.、Kuwano Kazuyoshi、Togashi Yosuke
  • Journal Title: Thoracic Cancer Volume: 12 Pages: 631～642
  • DOI: 10.1111/1759-7714.13839
  • Peer Reviewed / Open Access
• [Journal Article] Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens (2021)
  • Author(s): Kashima Yukie、Togashi Yosuke、Fukuoka Shota、et al.
  • Journal Title: Scientific Reports Volume: 11 Pages: 341
  • DOI: 10.1038/s41598-020-79385-w
  • Peer Reviewed / Open Access
• [Journal Article] Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants (2021)
  • Author(s): Arakawa Ayumu、Ichikawa Hitoshi、Kubo Takashi、、、、、Togashi Yosuke、et al.
  • Journal Title: New England Journal of Medicine Volume: 384 Pages: 42～50
  • DOI: 10.1056/NEJMoa2030391
  • Peer Reviewed
• [Journal Article] Heterogeneity in congenital melanocytic nevi contributes to multicentric melanomagenesis (2020)
  • Author(s): Honobe Akiko、Sakai Kazuko、Togashi Yosuke、Ohnuma Takehiro、Kawamura Tatsuyoshi、Nishio Kazuto、Inozume Takashi
  • Journal Title: Journal of Dermatological Science Volume: 100 Pages: 217～219
  • DOI: 10.1016/j.jdermsci.2020.09.004
  • Peer Reviewed
• [Journal Article] The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies (2020)
  • Author(s): Kumagai Shogo、Togashi Yosuke、Kamada Takahiro、et al.
  • Journal Title: Nature Immunology Volume: 21 Pages: 1346～1358
  • DOI: 10.1038/s41590-020-0769-3
  • Peer Reviewed
• [Journal Article] Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site (2020)
  • Author(s): Hayashi Hidetoshi、Takiguchi Yuichi、Minami Hironobu、Akiyoshi Kohei、Segawa Yoshihiko、Ueda Hiroki、Iwamoto Yasuo、Kondoh Chihiro、Matsumoto Koji、Takahashi Shin、Yasui Hisateru、Sawa Toshiyuki、Onozawa Yusuke、Chiba Yasutaka、Togashi Yosuke、et al.
  • Journal Title: JAMA Oncology Volume: 6 Pages: 1931～1931
  • DOI: 10.1001/jamaoncol.2020.4643
  • Peer Reviewed
• [Journal Article] The critical role of CD4+ T cells in PD-1 blockade against MHC-II?expressing tumors such as classic Hodgkin lymphoma (2020)
  • Author(s): Nagasaki Joji、Togashi Yosuke、Sugawara Takeaki、Itami Makiko、Yamauchi Nobuhiko、Yuda Junichiro、Sugano Masato、Ohara Yuuki、Minami Yosuke、Nakamae Hirohisa、Hino Masayuki、Takeuchi Masahiro、Nishikawa Hiroyoshi
  • Journal Title: Blood Advances Volume: 4 Pages: 4069～4082
  • DOI: 10.1182/bloodadvances.2020002098
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced tumor response to radiotherapy after PD-1 blockade in metastatic gastric cancer (2020)
  • Author(s): Sasaki Akinori、Nakamura Yoshiaki、Togashi Yosuke、et al.
  • Journal Title: Gastric Cancer Volume: 23 Pages: 893～903
  • DOI: 10.1007/s10120-020-01058-4
  • Peer Reviewed
• [Journal Article] Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial) (2020)
  • Author(s): Kawazoe Akihito、Kuboki Yasutoshi、Shinozaki Eiji、Hara Hiroki、Nishina Tomohiro、Komatsu Yoshito、Yuki Satoshi、Wakabayashi Masashi、Nomura Shogo、Sato Akihiro、Kuwata Takeshi、Kawazu Masahito、Mano Hiroyuki、Togashi Yosuke、Nishikawa Hiroyoshi、Yoshino Takayuki
  • Journal Title: Clinical Cancer Research Volume: 26 Pages: 5887～5894
  • DOI: 10.1158/1078-0432.CCR-20-1803
  • Peer Reviewed
• [Journal Article] An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells (2020)
  • Author(s): Kumagai Shogo、Togashi Yosuke、Sakai Chika、Kawazoe Akihito、Kawazu Masahito、Ueno Toshihide、Sato Eiichi、Kuwata Takeshi、Kinoshita Takahiro、Yamamoto Masami、Nomura Sachiyo、Tsukamoto Tetsuya、Mano Hiroyuki、Shitara Kohei、Nishikawa Hiroyoshi
  • Journal Title: Immunity Volume: 53 Pages: 187～203.e8
  • DOI: 10.1016/j.immuni.2020.06.016
  • Peer Reviewed
• [Journal Article] Association between the mutational smoking signature and the immune microenvironment in lung adenocarcinoma (2020)
  • Author(s): Sato Kei、Mimaki Sachiyo、Yamashita Riu、Togashi Yosuke、Naito Tomoyuki、Udagawa Hibiki、Katsumata Shinya、Nakasone Shoko、Miyoshi Tomohiro、Tane Kenta、Aokage Keiju、Sugano Masato、Kojima Motohiro、Fujii Satoshi、Kuwata Takeshi、Ochiai Atsushi、Goto Koichi、Tsuboi Masahiro、Tsuchihara Katsuya、Ishii Genichiro
  • Journal Title: Lung Cancer Volume: 147 Pages: 12～20
  • DOI: 10.1016/j.lungcan.2020.06.029
  • Peer Reviewed
• [Journal Article] Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603) (2020)
  • Author(s): Fukuoka Shota、Hara Hiroki、Takahashi Naoki、Kojima Takashi、Kawazoe Akihito、Asayama Masako、Yoshii Takako、Kotani Daisuke、Tamura Hitomi、Mikamoto Yuichi、Hirano Nami、Wakabayashi Masashi、Nomura Shogo、Sato Akihiro、Kuwata Takeshi、Togashi Yosuke、Nishikawa Hiroyoshi、Shitara Kohei
  • Journal Title: Journal of Clinical Oncology Volume: 38 Pages: 2053～2061
  • DOI: 10.1200/JCO.19.03296
  • Peer Reviewed
• [Journal Article] 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 (2020)
  • Author(s): Bando Hideaki、Kotani Daisuke、Tsushima Takahiro、Hara Hiroki、Kadowaki Shigenori、Kato Ken、Chin Keisho、Yamaguchi Kensei、Kageyama Shun-ichiro、Hojo Hidehiro、Nakamura Masaki、Tachibana Hidenobu、Wakabayashi Masashi、Fukutani Miki、Togashi Yosuke、Fuse Nozomu、Nishikawa Hiroyoshi、Kojima Takashi
  • Journal Title: BMC Cancer Volume: 20 Pages: 336
  • DOI: 10.1186/s12885-020-06716-5
  • Peer Reviewed / Open Access
• [Journal Article] The potential application of PD-1 blockade therapy for early-stage biliary tract cancer (2020)
  • Author(s): Umemoto Kumiko、Togashi Yosuke、Arai Yasuhito、Nakamura Hiromi、Takahashi Shinichiro、Tanegashima Tokiyoshi、Kato Mikiya、Nishikawa Tsubasa、Sugiyama Daisuke、Kojima Motohiro、Gotohda Naoto、Kuwata Takeshi、Ikeda Masafumi、Shibata Tatsuhiro、Nishikawa Hiroyoshi
  • Journal Title: International Immunology Volume: 32 Pages: 273～281
  • DOI: 10.1093/intimm/dxz080
  • Peer Reviewed / Open Access
• [Presentation] The Future of Immunotherapy (2021)
  • Author(s): Yosuke Togashi
  • Organizer: 2021 Targeted Therapy of Lung Cancer Meeting
  • Int'l Joint Research / Invited
• [Presentation] Clonal evolution in the tumor microenvironment (2021)
  • Author(s): Yosuke Togashi
  • Organizer: 第18回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] Phase II Trial of Site-Specific Treatment Based on Gene Expression and Mutation Profiling by next generation sequencing (NGS) for Patients (pts) With Cancer of Unknown Primary Site (CUP) (2021)
  • Author(s): Makoto Arai, Hidetoshi Hayashi, Hironobu Minami, Yuichi Takiguchi, Satomi Watanabe, Masanori Toyoda, Kohei Akiyoshi, Yoshihiko Segawa, Hiroki Ueda, Yasuo Iwamoto, Jun Masuda, Hirohumi Mukai, Toshio Kubo, Yosuke Togashi, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Yasutaka Chiba, Kazuto Nishio, and Kazuhiko Nakagawa.
  • Organizer: 第18回日本臨床腫瘍学会学術集会
• [Presentation] The critical role of CD4+ T cells in PD-1 blockade against MHC-II-expressing tumors such as classic Hodgkin lymphoma. (2021)
  • Author(s): Joji Nagasaki1, Yosuke Togashi, Takeaki Sugawara, Makiko Itami, Nobuhiko Yamauchi, Junichiro Yuda, Sugano Masato, Ohara Yuuki, Yosuke Minami, Hirohisa Nakamae, Masayuki Hino, Masahiro Takeuchi, Hiroyoshi Nishikawa.
  • Organizer: 第18回日本臨床腫瘍学会学術集会
• [Presentation] Heterogeneity in congenital melanocytic nevi contributes to muliticentric melanomagenesis. (2021)
  • Author(s): Takashi Inozume, Akiko Honobe, Kazuko Sakai, Yosuke Togashi, Takehiro Ohnura, Tatsuyoshi Kawamura, Kazuto Nishio
  • Organizer: 第18回日本臨床腫瘍学会学術集会
• [Presentation] Efficacy Predictors of Preoperative CRT and Consolidation Nivolumab in Patients with Locally Advanced Rectal Cancer (2021)
  • Author(s): Koji Inamori, Yosuke Togashi, Hideaki Bando, Yuichiro Tsukada, Shota Fukuoka,Yutaka Suzuki, Daisuke Kotani, Motohiro Kojima, Makoto Fukui, Satoshi Yuki, Yoshito Komatsu, Shigenori Homma, Akinobu Taketomi, Mamoru Uemura, Takeshi Kato, Masaaki Ito, Hiroyoshi Nishikawa, Takayuki Yoshino.
  • Organizer: 第18回日本臨床腫瘍学会学術集会
• [Presentation] TIGIT/CD155 axis mediates resistance to immunotherapies in inflamed tumors. (2021)
  • Author(s): Shusuke Kawashima, Takashi Inozume, Masahito Kawazu, Etsuko Tanji, Akiko Honobe, Takehiro Ohnuma, Tatsuyoshi Kawamura, Hiroyuki Matsue, Yosuke Togashi.
  • Organizer: 第18回日本臨床腫瘍学会学術集会
• [Presentation] Emerging biomarker for immunotherapy in head and neck cancer (2021)
  • Author(s): Yosuke Togashi
  • Organizer: 第18回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] Translational Research of VOLTAGE-A: Efficacy Predictors of Preoperative Chemoradiotherapy and Consolidation Nivolumab in Patients with both Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer (2021)
  • Author(s): Koji Inamori, Yosuke Togashi, Hideaki Bando, Yuichiro Tsukada, Shota Fukuoka, Ayako Suzuki, Yutaka Suzuki, Daisuke Kotani, Motohiro Kojima, Makoto Fukui, Satoshi Yuki, Yoshito Komatsu, Shigenori Homma, Akinobu Taketomi, Mamoru Uemura, Takeshi Kato, Masaaki Ito, Hiroyoshi Nishikawa, Takayuki Yoshino.
  • Organizer: ASCO-GI2021
  • Int'l Joint Research
• [Presentation] 腫瘍に発現するPD-L2の免疫抑制機能について (2020)
  • Author(s): 種子島 時祥, 冨樫 庸介, 東 公一, 入江 拓磨, 木下 史生, 柏木 英志, 武内 在雄, 立神 勝則, 江藤 正俊, 西川 博嘉
  • Organizer: 第108回日本泌尿器科学総会
• [Presentation] PD-L2による、自発的・治療関連抗腫瘍免疫に対する免疫抑制機能 (2020)
  • Author(s): 種子島 時祥, 冨樫 庸介, 江藤 正俊, 西川 博嘉
  • Organizer: 第72回西日本泌尿器科学総会
• [Presentation] Translational Research using Clinical Samples in Cancer Immunology (2020)
  • Author(s): Yosuke Togashi
  • Organizer: 第79回日本癌学会学術総会
  • Invited
• [Presentation] 免疫チェックポイント阻害剤と制御性T細胞 (2020)
  • Author(s): 冨樫庸介
  • Organizer: 第24回日本がん分子標的治療学会
  • Invited
• [Presentation] 免疫チェックポイント阻害剤を含む併用療法におけるバイオマーカー (2020)
  • Author(s): 冨樫庸介
  • Organizer: 第60回日本呼吸器学会学術講演会
  • Invited
• [Presentation] Cancer immunogenomics (2020)
  • Author(s): Yosuke Togashi
  • Organizer: KSMO and JSMO Joint Symposium
  • Int'l Joint Research / Invited
• [Presentation] Translational Research for Future Immunotherapy (2020)
  • Author(s): 冨樫庸介
  • Organizer: 第92回日本胃癌学会総会
  • Invited
• [Presentation] Translational research of voltage-A1: Efficacy predictors of preoperative chemoradiotherapy and subsequent nivolumab monotherapy in patients with microsatellite-stable locally advanced rectal cancer (2020)
  • Author(s): Koji Inamori, Yosuke Togashi, Hideaki Bando, Yuichiro Tsukada, Shota Fukuoka, Ayako Suzuki, Yutaka Suzuki, Daisuke Kotani, Motohiro Kojima, Makoto Fukui, Satoshi Yuki, Yoshito Komatsu, Shigenori Homma, Akinobu Taketomi, Mamoru Uemura, Takeshi Kato, Masaaki Ito, Hiroyoshi Nishikawa, Takayuki Yoshino
  • Organizer: ASCO2020
  • Int'l Joint Research
• [Presentation] Short-Term Results of VOLTAGE-A: Nivolumab Monotherapy and Subsequent Radical Surgery Following Preoperative Chemoradiotherapy in Patients with Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer. (2020)
  • Author(s): Satoshi Yuki, Hideaki Bando, Yuichiro Tsukada, Koji Inamori, Yoshito Komatsu, Shigenori Homma, Mamoru Uemura, Takeshi Kato, Daisuke Kotani, Shota Fukuoka, Naoki Nakamura, Makoto Fukui, Masashi Wakabayashi, Motohiro Kojima, Yosuke Togashi, Akihiro Sato, Hiroyoshi Nishikawa, Masaaki Ito, Takayuki Yoshino
  • Organizer: ASCO2020
  • Int'l Joint Research