NKT cell-targeted cancer immunotherapy based on the comprehension of anti-tumor immune response in the lung cancer microenvironment

• Project/Area Number: 18H02892
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Chiba University
• Principal Investigator: MOTOHASHI Shinichiro 千葉大学, 大学院医学研究院, 教授 (60345022)
• Co-Investigator(Kenkyū-buntansha): 木村 元子 千葉大学, 大学院医学研究院, 准教授 (00345018)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
• Keywords: 免疫療法 / 肺癌 / 抗腫瘍免疫抑制

Outline of Final Research Achievements

The purpose of this study is to develop a new cancer immunotherapy for lung cancer by understanding the immune response occurring in the tumor environment including regional lymph nodes that are metastasis routes of cancer. The novel T cell population found in this study expresses markers associated with tissue residency in regional lymph nodes of lung cancer, and can be related to the pathophysiology and progression of lung cancer. In addition, we identified multiple protein candidates, which are produced from tumor cell lines to be responsible for the suppression of anti-tumor immune responses.
In the future, we aim to clarify the mechanism of action and the method to overcome the suppression of anti-cancer immune responses toward the development of a new cancer immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

今回発見した新たなT細胞集団が、肺癌の病態や進行と関連している可能性があり、このT細胞をモニターすることで、治療の効果判定や適切な治療法選択のマーカーとなる可能性がある。また腫瘍から産生される免疫抑制タンパク質を介した免疫抑制状態を解除することが可能となれば、全身的な免疫状態の改善につながり、標準治療となったがん免疫療法の有効性を大きく改善する可能性が高く、がん治療の成績向上に貢献する。

Research Products

• [Journal Article] A phase I study of loco-regional immunotherapy by transbronchial injection of α-galactosylceramide-pulsed antigen presenting cells in patients with lung cancer (2020)
  • Author(s): Ishibashi Fumihiro、Sakairi Yuichi、Iwata Takekazu、Moriya Yasumitsu、Mizobuchi Teruaki、Hoshino Hidehisa、Yoshida Shigetoshi、Hanaoka Hideki、Yoshino Ichiro、Motohashi Shinichiro
  • Journal Title: Clinical Immunology Volume: 215 Pages: 108457-108457
  • DOI: 10.1016/j.clim.2020.108457
  • Peer Reviewed
• [Journal Article] Activated invariant natural killer T cells directly recognize leukemia cells in a CD1d‐independent manner (2020)
  • Author(s): Aoki Takahiro、Takami Mariko、Takatani Tomozumi、Motoyoshi Kiwamu、Ishii Ayana、Hara Ayaka、Toyoda Takahide、Okada Reona、Hino Moeko、Koyama‐Nasu Ryo、Kiuchi Masahiro、Hirahara Kiyoshi、Kimura Motoko Y.、Nakayama Toshinori、Shimojo Naoki、Motohashi Shinichiro
  • Journal Title: Cancer Science Volume: 111 Issue: 7 Pages: 2223-2233
  • DOI: 10.1111/cas.14428
  • Peer Reviewed / Open Access
• [Journal Article] Differential gene analysis during the development of obliterative bronchiolitis in a murine orthotopic lung transplantation model: A comprehensive transcriptome-based analysis (2020)
  • Author(s): Hata A、Suzuki H、Nakajima T、Fujiwara T、Shiina Y、Kaiho T、Toyoda T、Inage T、Ito T、Sakairi Y、Tamura H、Wada H、Yamada Y、Chiyo M、Matsusaka K、Fukuyo M、Shinohara K、Itoga S、Motohashi S、Matsushita K、Kaneda A、Yoshino I
  • Journal Title: PLOS ONE Volume: 15 Issue: 5 Pages: 0232884-0232884
  • DOI: 10.1371/journal.pone.0232884
  • Peer Reviewed / Open Access
• [Journal Article] Essential Role for CD30-Transglutaminase 2 Axis in Memory Th1 and Th17 Cell Generation (2020)
  • Author(s): Suzuki Akane S.、Yagi Ryoji、Kimura Motoko Y.、Iwamura Chiaki、Shinoda Kenta、Onodera Atsushi、Hirahara Kiyoshi、Tumes Damon J.、Koyama-Nasu Ryo、Iismaa Siiri E.、Graham Robert M.、Motohashi Shinichiro、Nakayama Toshinori
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 1536-1536
  • DOI: 10.3389/fimmu.2020.01536
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD1d expression in glioblastoma is a promising target for NKT cell-based cancer immunotherapy (2020)
  • Author(s): Hara Ayaka、Koyama-Nasu Ryo、Takami Mariko、Toyoda Takahide、Aoki Takahiro、Ihara Fumie、Kobayashi Masayoshi、Hirono Seiichiro、Matsutani Tomoo、Nakayama Toshinori、Iwadate Yasuo、Motohashi Shinichiro
  • Journal Title: Cancer Immunology, Immunotherapy Volume: - Issue: 5 Pages: 1239-1254
  • DOI: 10.1007/s00262-020-02742-1
  • Peer Reviewed / Open Access
• [Journal Article] Phase II study of α-galactosylceramide-pulsed antigen-presenting cells in patients with advanced or recurrent non-small cell lung cancer (2020)
  • Author(s): Toyoda, T., Kamata, T., Tanaka, K., Ihara, F., Takami, M., Suzuki, H., Nakajima, T., Ikeuchi, T., Kawasaki, Y., Hanaoka, H., Nakayama, T., Yoshino, I., and Motohashi, S.
  • Journal Title: J. Immunother. Cancer Volume: 8 Issue: 1 Pages: e000316-e000316
  • DOI: 10.1136/jitc-2019-000316
  • Peer Reviewed / Open Access
• [Journal Article] Immunological Features of a Lung Cancer Patient Achieving an Objective Response with Anti-PD-1 Blockade Therapy (2019)
  • Author(s): Kamata, T., Yoshida, S., Takami, M., Ihara, F., Yoshizawa, H., Toyoda, T., Takeshita, Y., Nobuyama, S., Kanetsuna, Y., Sato, T., Yoshino, I., and Motohashi, S.
  • Journal Title: Cancer Sci. Volume: 111 Issue: 1 Pages: 288-296
  • DOI: 10.1111/cas.14222
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory T cells induce CD4－ NKT cell anergy and suppress NKT cell cytotoxic function (2019)
  • Author(s): Ihara, F., Sakurai, D., Takami, M., Kamata, T., Kunii, N., Yamasaki, K., Iinuma, T., Nakayama, T., Motohashi, S., and Okamoto, Y.
  • Journal Title: Cancer Immunol. Immunother Volume: 68 Issue: 12 Pages: 1935-1947
  • DOI: 10.1007/s00262-019-02417-6
  • Peer Reviewed / Open Access
• [Journal Article] Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation (2019)
  • Author(s): Harada, K., Ihara, F., Takami, M., Kamata, T., Mise, N., Yoshizawa, H., Hishiki, T., Saito, T., Terui, K., Nakata, M., Komatsu, S., Ikeuchi, T., Nakayama, T., Yoshida, H., Motohashi, S.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 3 Pages: 888-902
  • DOI: 10.1111/cas.13933
  • Peer Reviewed / Open Access
• [Journal Article] Immunosuppressive property of submandibular lymph nodes in patients with head and neck tumors: differential distribution of regulatory T cells (2018)
  • Author(s): Sakurai D, Uchida R, Ihara F, Kunii N, Nakagawa T, Chazono H, Hanazawa T, Motohashi S, Okamoto Y
  • Journal Title: BMC Research Notes Volume: 11 Issue: 1 Pages: 479-479
  • DOI: 10.1186/s13104-018-3587-z
  • Peer Reviewed / Open Access
• [Journal Article] Crucial role of CD69 in anti-tumor immunity through regulating the exhaustion of tumor-infiltrating T cells (2018)
  • Author(s): Mita Y, Kimura MY, Hayashizaki K, Koyama-Nasu R, Ito T, Motohashi S, Okamoto Y & Nakayama T
  • Journal Title: International Immunology Volume: 30 Issue: 12 Pages: 559-567
  • DOI: 10.1093/intimm/dxy050
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Application of iNKT Cell-mediated Anti-tumor Activity Against Lung Cancer and Head and Neck Cancer (2018)
  • Author(s): Takami, M., Ihara, F., Motohashi, S.
  • Journal Title: Front. Immunol. Volume: 7 Pages: 2021-2021
  • DOI: 10.3389/fimmu.2018.02021
  • Peer Reviewed / Open Access
• [Journal Article] CD69 prevents PLZFhi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation (2018)
  • Author(s): Kimura Motoko Y.、Igi Akemi、Hayashizaki Koji、Mita Yukiyoshi、Shinzawa Miho、Kadakia Tejas、Endo Yukihiro、Ogawa Satomi、Yagi Ryoji、Motohashi Shinichiro、Singer Alfred、Nakayama Toshinori
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 3749-3749
  • DOI: 10.1038/s41467-018-06283-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Co-stimulatory Signaling Influences TGF-β-Dependent CD4+ T cell Differentiation and Its Plasticity (2018)
  • Author(s): Takami, M., Iwashima, M., Motohashi, S.
  • Journal Title: Chiba Survey Research Journal Volume: 7 Pages: 80-87
  • NAID: 40021727410
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of leukotriene B4 12-hydroxydehydrogenase in α-galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer (2018)
  • Author(s): Tanaka K, Kanesaka Y, Takami M, Suzuki A, Hosokawa H, Onodera A, Kamata T, Nagato K, Nakayama T, Yoshino I, Motohashi S
  • Journal Title: Biochem Biophys Res Commun. Volume: 506(1) Issue: 1 Pages: 27-32
  • DOI: 10.1016/j.bbrc.2018.10.048
  • Peer Reviewed
• [Journal Article] TGF-β suppresses RasGRP1 expression and supports regulatory T cells resistance against p53-induced CD28-dependent T cell apoptosis (2018)
  • Author(s): Takami, M., Cunha, C., Motohashi , S., Nakayama, T., Iwashima, M.
  • Journal Title: Eur. J. Immunol. Volume: 48 Issue: 12 Pages: 1938-1943
  • DOI: 10.1002/eji.201847587
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Activated iNKT cells enhance the anti-tumor effect of antigen specific CD8 T cells on mesothelin-expressing salivary gland cancer (2018)
  • Author(s): Makita Yuji、Kunii Naoki、Sakurai Daiju、Ihara Fumie、Motohashi Shinichiro、Suzuki Akane、Nakayama Toshinori、Okamoto Yoshitaka
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 1254-1254
  • DOI: 10.1186/s12885-018-5179-7
  • Peer Reviewed / Open Access
• [Presentation] Clinical Application of iPS cell-derived NKT cells to cancer immunotherapy (2021)
  • Author(s): 本橋 新一郎
  • Organizer: 千葉グローバル・ヘルスケアビジネス・フォーラム2021
  • Invited
• [Presentation] iPS細胞由来NKT細胞を利用したがん免疫療法の開発 (2021)
  • Author(s): 本橋 新一郎
  • Organizer: リプロセル講演会
  • Invited
• [Presentation] Adjuvant effect of NK cells on the anti-tumor activity of NKT cells (2020)
  • Author(s): Takami, M., Ishii, A., Motohashi, S.
  • Organizer: 第24回日本がん免疫学会総会
• [Presentation] iPS細胞を利用したがん免疫療法の医師主導治験 (2020)
  • Author(s): 本橋 新一郎
  • Organizer: 第41回日本臨床薬理学会学術総会
  • Invited
• [Presentation] Cancer Immunotherapy-from basic research of NKT cell to clinical fields- (2019)
  • Author(s): 本橋 新一郎
  • Organizer: THE REACTA FORUM 2019
  • Int'l Joint Research / Invited
• [Presentation] 膠芽腫に発現するCD1d分子はNKT細胞を用いた免疫療法における有望な標的となる (2019)
  • Author(s): 原彩佳, 那須亮, 高見真理子, 小林正芳, 廣野誠一郎, 松谷智郎, 中山俊憲, 本橋新一郎, 岩立康男
  • Organizer: 日本脳神経外科学会第78回学術総会
• [Presentation] CD1d expression in glioblastoma is a promising target for NKT cell- based cancer immunotherapy (2019)
  • Author(s): Hara, A., Nasu, R., Takami, M., Hirono, S., Matsutani, T., Nakayama, T., Iwadate, Y., Motohashi, S.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] α-Galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer (2019)
  • Author(s): Motohashi, S.
  • Organizer: 2019 International Symposium for Cell-based Translational Medicine and Clinical Application :The 4th TMU International Symposium for Cell Therapy and Regenerative Medicine
  • Int'l Joint Research / Invited
• [Presentation] CD1d expression in glioblastoma is a promising target for NKT cell- based cancer immunotherapy (2019)
  • Author(s): Hara, A., Nasu, R., Takami, M., Hirono, S., Matsutani, T., Nakayama, T., Iwadate, Y., Motohashi, S.
  • Organizer: EMBO workshop CD1-MR1
  • Int'l Joint Research
• [Presentation] Invariant NKT cells target CD1d-negative leukemia cells with TCR and NK receptors (2019)
  • Author(s): Aoki, T., Takami, M., Takatani, T., Motoyoshi, K., Ishii, A., Hara, A., Hino, M., Shimojo, N., Motohashi, S.
  • Organizer: EMBO workshop CD1-MR1
  • Int'l Joint Research
• [Presentation] Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation (2019)
  • Author(s): Yoshizawa, H., Harada, K., Ishii, A., Mise, N., Hishiki, T., Saito, K., Nakata, M., Komatsu, S., Nakayama, T., Yoshida, H., Takami, M., Motohashi, S.
  • Organizer: EMBO workshop CD1-MR1
  • Int'l Joint Research
• [Presentation] NK cells enhance the anti-tumor activity of NKT cells (2019)
  • Author(s): Takami, M., Ihara, F., Ishii, A., Motohashi, S.
  • Organizer: EMBO workshop CD1-MR1
  • Int'l Joint Research
• [Presentation] Invariant NKT cells recognize leukemia cells in a CD1d independent manner (2019)
  • Author(s): 青木 孝浩, 高見 真理子, 高谷 具純, 本吉 究, 石井 絢菜, 岡田 玲緒奈, 日野 もえ子, 下条 直樹, 本橋 新一郎
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] 膠芽腫に発現するCD1d分子はNKT細胞を用いた免疫療法における有望な標的となる (2019)
  • Author(s): 原 彩佳, 那須 亮, 高見 真理子, 廣野 誠一郎, 松谷 智郎, 中山 俊憲, 岩立 康男, 本橋 新一郎
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation (2019)
  • Author(s): 原田和明, 吉澤比呂子, 三瀬直子, 小松秀吾, 中田光政, 照井慶太, 齋藤武, 石井絢菜, 高見真理子, 吉田英生, 本橋新一郎
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] 標準治療となったがん免疫療法の今後の展望 (2019)
  • Author(s): 本橋 新一郎
  • Organizer: 第57回ニューロ・オンコロジィの会
  • Invited
• [Presentation] 神経芽腫細胞由来の液性因子による樹状細胞への抑制効果の検討 (2019)
  • Author(s): 原田 和明, 齋藤 武, 照井 慶太, 中田 光政, 小松 秀吾, 秦 佳孝, 吉澤 比呂子, 工藤 渉, 古金 遼也, 高見 真理子, 本橋 新一郎, 吉田 英生
  • Organizer: 第56回日本小児外科学会学術集会
• [Presentation] マスサイトメトリーによる肺癌所属リンパ節の免疫細胞解析 (2019)
  • Author(s): 豊田 行英, 本橋 新一郎, 植松 靖文, 清水 大貴, 今林 宏樹, 小野里 優希, 松本 寛樹, 伊藤 祐輝, 海寳 大輔, 椎名 裕樹, 佐田 諭己, 山本 高義, 田中 教久, 坂入 祐一, 和田 啓伸, 鈴木 秀海, 中島 崇裕, 吉野 一郎
  • Organizer: 第36回日本呼吸器外科学会学術集会
• [Presentation] NKT cell-targeted immunotherapy for non-small cell lung cancer (2019)
  • Author(s): Motohashi, S.
  • Organizer: 2019 Forum for TMU Research Center for Cell Therapy and Regeneration Medicine(CCTRM)
  • Int'l Joint Research / Invited
• [Presentation] がん免疫療法の最前線 (2019)
  • Author(s): 本橋新一郎
  • Organizer: 松戸ゐのはな会総会
  • Invited
• [Presentation] Double-Stranded RNA Derived from Lactic Acid Bacteria Augments Th1 Immunity via Interferon-β from Human Dendritic Cells (2018)
  • Author(s): Ikari, N., Kawashima, T., Kubota, Y., Motohashi, S., Shimojo, N., Tsuji, N. M.
  • Organizer: International Symposium of International Scientific Association for Probiotics and Prebiotics 2018
  • Int'l Joint Research
• [Presentation] がん免疫療法の最先端 (2018)
  • Author(s): 本橋新一郎
  • Organizer: 上総イムノオンコロジーセミナー
  • Invited
• [Presentation] NKT 細胞を用いたがん免疫療法 (2018)
  • Author(s): 本橋新一郎
  • Organizer: 第16回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] 頭頸部扁平上皮癌患者における制御性T細胞の臨床的意義 (2018)
  • Author(s): 伊原 史英、高見真理子、國井 直樹、櫻井 大樹、岡本 美孝、本橋 新一郎
  • Organizer: 第22回日本がん免疫学会総会
• [Presentation] Crucial role for CD69 in anti-tumor immunity (2018)
  • Author(s): Mita, Y., Kimura, M., Nasu, R., Motohashi, S., Okamoto, Y., Nakayama, T.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Anti-tumor immunity via the superoxide-eosinophil axis induced by lipophilic component of Mycobacterium lipomannan (2018)
  • Author(s): Ito, T., Hirahara, K., Nasu, R., Yano, I., Motohashi, S., Nakayama, T.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] The analysis of Th2 cell subsets in house dust mite allergic rhinitis patients after sublingual immunotherapy (2018)
  • Author(s): Ihara, F., Takami, M., Kunii N., Sakurai, D., Motohashi S., Nakayama T., Okamoto Y
  • Organizer: 第3回千葉大学グローバルプロミネント研究基幹シンポジウム
• [Presentation] 原発性肺癌に対するNKT細胞を用いた免疫療法-第II相試験- (2018)
  • Author(s): 本橋新一郎
  • Organizer: 千葉大学・琉球大学合同治療学推進シンポジウム
  • Invited
• [Presentation] 肺癌に対するα-Galactosylceramideパルス樹状細胞を用いた第Ⅱ相臨床試験 (2018)
  • Author(s): 本橋新一郎
  • Organizer: 第24回日本エンドトキシン・自然免疫研究会
  • Invited
• [Presentation] Role of CD69 on iNKT cell development in the thymus (2018)
  • Author(s): Kimura, M. Y., Hayashizaki, K., Yagi, R., Endo, Y., Motohashi, S., Nakayama, T.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] A Phase II study of α-Galactosylceramide-pulsed antigen presenting cells for advanced or recurrent non-small cell lung cancer (2018)
  • Author(s): Motohashi, S., Kamata, T., Toyoda, T., Tanaka, T., Ihara, F., Takami, M., Yosino, I., Nakayama, T.
  • Organizer: 第47回日本免疫学会学術集会