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Elucidation of the molecular mechanism of memory T cell exhaustion and development of its reprogramming method

Research Project

Project/Area Number 22K19444
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 49:Pathology, infection/immunology, and related fields
Research InstitutionKeio University

Principal Investigator

Yoshimura Akihiko  慶應義塾大学, 医学部(信濃町), 教授 (90182815)

Project Period (FY) 2022-06-30 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2023: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2022: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Keywords腫瘍免疫 / T細胞 / 免疫記憶 / 疲弊 / 転写因子 / CAR-T
Outline of Research at the Start

記憶T細胞は慢性炎症や腫瘍環境では持続的な抗原刺激と何らかの環境因子によって疲弊状態(exhaustion)に陥る。結果的に疲弊化はがんにおける免疫チェックポイント療法の感受性を下げることになる。本研究は、メモリーT細胞の最終分化段階である「疲弊」の分子メカニズムを明らかにするとともに、これを解除ないし分化転換(リプログラミング)する方法を開発するものである。具体的には転写因子NR4aを中心に、腫瘍特異的な疲弊化メモリーT細胞を用いて疲弊化に重要な遺伝子を破壊ないし強制発現して、幹細胞性をもつステムセルメモリーT細胞(Tscm)に転換させる方法を開発する。

Outline of Final Research Achievements

Memory T cells play a central role in tumor immunity, but in the tumor environment T cells become exhausted and fail to exert sufficient antitumor effects. We have identified the NR4a family of transcription factors that play a central role in T cell exhaustion. In this study, we used genetically engineered mice and single-cell RNA sequencing to examine how NR4a affects T cell memory differentiation and whether deletion of NR4a can unexhaust T cells and reprogram them to young memory T cells. The results showed that NR4a deficiency not only suppresses exhaustion but also converts T cells to young memory cells.

Academic Significance and Societal Importance of the Research Achievements

これまで不明であったT細胞疲弊の分子機構の一端がNR4aを中心に初めて明らかにされた。さらにNR4aを阻害することで疲弊を解除するだけでなく、若いメモリーT細胞に転換できることを示たことは、T細胞分化の基礎研究のみならず、NR4aが抗腫瘍免疫の強力な標的分子になりうることを示せた意義は大きい。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (27 results)

All 2024 2023 2022 Other

All Int'l Joint Research (4 results) Journal Article (9 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (10 results) (of which Int'l Joint Research: 4 results,  Invited: 9 results) Book (2 results) Remarks (2 results)

  • [Int'l Joint Research] University de Sherbrooke(カナダ)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Massachusetts Institute of Technology(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Massachusetts Institute of Technology(米国)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] University de Sherbrooke(カナダ)

    • Related Report
      2022 Research-status Report
  • [Journal Article] NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment2024

    • Author(s)
      Srirat Tanakorn、Hayakawa Taeko、Mise-Omata Setsuko、Nakagawara Kensuke、Ando Makoto、Shichino Shigeyuki、Ito Minako、Yoshimura Akihiko
    • Journal Title

      Cell Reports

      Volume: 43 Issue: 3 Pages: 113898-113898

    • DOI

      10.1016/j.celrep.2024.113898

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition2024

    • Author(s)
      Tokifuji Yukiko、Hayabuchi Hodaka、Sasaki Takashi、Hara-Chikuma Mariko、Hirota Keiji、Takahashi Hayato、Amagai Masayuki、Yoshimura Akihiko、Chikuma Shunsuke
    • Journal Title

      iScience

      Volume: 27 Issue: 1 Pages: 108646-108646

    • DOI

      10.1016/j.isci.2023.108646

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aberrant expression of suppressor of cytokine signaling (<scp>SOCS</scp>) molecules contributes to the development of allergic diseases2023

    • Author(s)
      Jafarzadeh Abdollah、Chauhan Prashant、Nemati Maryam、Jafarzadeh Sara、Yoshimura Akihiko
    • Journal Title

      Clinical &amp; Experimental Allergy

      Volume: 53 Issue: 11 Pages: 1147-1161

    • DOI

      10.1111/cea.14385

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] SOCS3 deletion in effector T?cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine2023

    • Author(s)
      Mise-Omata Setsuko、Ando Makoto、Srirat Tanakorn、Nakagawara Kensuke、Hayakawa Taeko、Iizuka-Koga Mana、Nishimasu Hiroshi、Nureki Osamu、Ito Minako、Yoshimura Akihiko
    • Journal Title

      Cell Reports

      Volume: 42 Issue: 8 Pages: 112940-112940

    • DOI

      10.1016/j.celrep.2023.112940

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DNA-damaged podocyte-CD8 T?cell crosstalk exacerbates kidney injury by altering DNA methylation2023

    • Author(s)
      Nakamichi Ran、Hishikawa Akihito、Chikuma Shunsuke、Yoshimura Akihiko、Sasaki Takashi、Hashiguchi Akinori、Abe Takaya、Tokuhara Tomoko、Yoshimoto Norifumi、Nishimura Erina Sugita、Hama Eriko Yoshida、Azegami Tatsuhiko、Nakayama Takashin、Hayashi Kaori、Itoh Hiroshi
    • Journal Title

      Cell Reports

      Volume: 42 Issue: 4 Pages: 112302-112302

    • DOI

      10.1016/j.celrep.2023.112302

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation2023

    • Author(s)
      Khan, M. G. M., N. Boufaied, M. Yeganeh, R. Kandhi, S. Petkiewicz, A. Sharma, A. Yoshimura, G. Ferbeyre, D. P. Labb, S. , S. Ramanathan, and S. Ilangumaran.
    • Journal Title

      Cancers (Basel)

      Volume: 15 Issue: 3 Pages: 905-905

    • DOI

      10.3390/cancers15030905

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Essential roles of the transcription factor NR4A1 in regulatory T cell differentiation under the influence of immunosuppressants2022

    • Author(s)
      Takashi Sekiya, Hidenori Kasahara, Ryo Takemura, Shinya Fujita, Jun Kato, Noriko Doki, Yuta Katayama, Yukiyasu Ozawa, Satoru Takada, Tetsuya Eto, Takahiro Fukuda, Tatsuo Ichinohe, Minoko Takanashi, Makoto Onizuka, Yoshiko Atsuta, Shinichiro Okamoto, Akihiko Yoshimura, Satoshi Takaki, Takehiko Mori
    • Journal Title

      The Journal of Immunology

      Volume: in press Issue: 9 Pages: 2122-2130

    • DOI

      10.4049/jimmunol.2100808

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Memory B Cells and Memory T Cells Induced by SARS-CoV-2 Booster Vaccination or Infection Show Different Dynamics and Responsiveness to the Omicron Variant2022

    • Author(s)
      Mise-Omata, S., M. Ikeda, M. Takeshita, Y. Uwamino, M. Wakui, T. Arai, A. Yoshifuji, K. Murano, H. Siomi, K. Nakagawara, M. Ohyagi, M. Ando, N. Hasegawa, H. Saya, M. Murata, K. Fukunaga, H. Namkoong, X. Lu, S. Yamasaki, and A. Yoshimura.
    • Journal Title

      J Immunol

      Volume: 209 Issue: 11 Pages: 2104-2113

    • DOI

      10.4049/jimmunol.2200525

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes2022

    • Author(s)
      Wang, T. W., Y. Johmura, N. Suzuki, S. Omori, T. Migita, K. Yamaguchi, S. Hatakeyama, S. Yamazaki, E. Shimizu, S. Imoto, Y. Furukawa, A. Yoshimura, and M. Nakanishi
    • Journal Title

      Nature

      Volume: 611 Issue: 7935 Pages: 358-364

    • DOI

      10.1038/s41586-022-05388-4

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 細胞の疲弊と老化を司る転写因子 NR4a2024

    • Author(s)
      吉村昭彦
    • Organizer
      ゲノム創薬・創発フォーラム 第12回シンポジウム
    • Related Report
      2023 Annual Research Report
  • [Presentation] Molecular Mechanism of Immunological Tolerance by SOCS and NR4a2023

    • Author(s)
      Akihiko Yoshimura
    • Organizer
      4th International Conference on Cell and Experimental Biology
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] he role of NR4a transcription factors in regulating the fate and function of regulatory T cells and cytotoxic T cells2023

    • Author(s)
      Akihiko Yoshimura
    • Organizer
      Finnish Japanese joint symposium 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] サイトカインシグナル制御のrevisit2023

    • Author(s)
      吉村昭彦
    • Organizer
      第60回日本消化器免疫学会総会 特別講演
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] NR4aを標的としたT細胞疲弊の解除2023

    • Author(s)
      吉村昭彦
    • Organizer
      第13回シグナルネットワーク研究会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] T細胞の疲弊と老化を司る転写因子; NR4a2023

    • Author(s)
      吉村昭彦
    • Organizer
      ゲノム創薬・創発フォーラム第12回シンポジウム
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] SOCS, SPRED and NR4a:Negative regulators of cytokine signaling and transcription in immune tolerance2022

    • Author(s)
      Akihiko Yoshimura
    • Organizer
      ICIS2022
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] NR4aによるT細胞疲弊機構とその解除による抗腫瘍免疫増強2022

    • Author(s)
      吉村昭彦、安藤眞、Tanakorn Srirat
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] T細胞の老化、疲弊化と疾患2022

    • Author(s)
      吉村昭彦
    • Organizer
      国際個別化医療学会第27回学術集会
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] T細胞疲弊の解除による抗腫瘍効果増強2022

    • Author(s)
      吉村 昭彦, 安藤 眞, 中川原 賢亮, 三瀬 節子
    • Organizer
      第43回日本炎症・再生医学会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Book] 免疫「超」入門2023

    • Author(s)
      吉村昭彦
    • Total Pages
      256
    • Publisher
      講談社
    • ISBN
      4065340373
    • Related Report
      2023 Annual Research Report
  • [Book] Advances in Immunology, Vol.1572023

    • Author(s)
      Akihiko Yoshimura他
    • Total Pages
      198
    • Publisher
      ACADEMIC PRESS, INC.
    • ISBN
      9780443193286
    • Related Report
      2022 Research-status Report
  • [Remarks] がんに対して悪玉サイトカインであるIL-6の作用を善玉に変えることに成功

    • URL

      https://www.keio.ac.jp/ja/press-releases/2023/8/17/28-144531/

    • Related Report
      2023 Annual Research Report
  • [Remarks] 疲弊したT細胞を若返らせ、強い抗腫瘍効果をもつT細胞の作製に成功

    • URL

      https://www.keio.ac.jp/ja/press-releases/2021/10/20/28-83203/

    • Related Report
      2022 Research-status Report

URL: 

Published: 2022-07-05   Modified: 2025-01-30  

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