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The nature of exhausted CD4+ T cells in the tumor microenvironment

Research Project

Project/Area Number 22K20824
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0901:Oncology and related fields
Research InstitutionOkayama University

Principal Investigator

Nagasaki Joji  岡山大学, 医歯薬学域, 研究准教授 (20955447)

Project Period (FY) 2022-08-31 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords濾胞性ヘルパーT細胞 / 腫瘍微小環境 / 疲弊 / 腫瘍特異的T細胞 / 細胞傷害性T細胞 / がん免疫 / 免疫チェックポイント阻害薬 / exhausted CD4陽性T細胞 / 腫瘍浸潤リンパ球 / CD4陽性T細胞 / exhaustion
Outline of Research at the Start

腫瘍微小環境(TME)で抗腫瘍免疫応答に重要な腫瘍特異的CD8陽性T細胞はexhaustionの状態で、そこでは細胞傷害性CD4陽性T細胞も重要であることを申請者は示した。さらにTMEの濾胞性ヘルパーT細胞(TFH)の一部に細胞傷害活性を有する新規の細胞集団を認め、非細胞傷害性TFHとの比較からprogenitor/terminal exhaustionの概念がCD4陽性T細胞にも存在する可能性を見出した。本研究は細胞傷害性TFH様細胞という新規細胞概念を確立し、CD4陽性T細胞のexhaustionの再定義を目的としており、抗腫瘍免疫応答の本体解明、治療標的・バイオマーカー同定につながる。

Outline of Final Research Achievements

We found a novel population of cytotoxic TFH-like cells in TME, which directly attack tumor cells. Comparing the gene expression between the conventional non-cytotoxic TFH and the novel cytotoxic TFH-like cells, we identified the former showed TCF1 high and BLIMP1 low phenotypes, while the latter TCF1 low and BLIMP1 high, which are similar to progenitor exhaustion/ terminally differentiated exhaustion in CD8+ T cells. The in vitro functional analysis showed that TCF1 over-expressed or BLIMP1 knocked down TFH cells secreted a smaller volume of granzyme B, which suggests the concept is similar to that of CD8+ T cell exhaustion.

Academic Significance and Societal Importance of the Research Achievements

本研究ではTMEのTFHの中に細胞傷害活性を有するTFH様細胞が存在することを新たに見出し、従来型TFHと細胞傷害性TFH様細胞とは、CD8陽性T細胞におけるprogenitor exhaustion とterminally differentiated exhaustionの関係と同様であることを明らかにした。本研究により今まで明らかではなかったCD4陽性T細胞におけるexhaustionを再定義することができ、抗腫瘍免疫応答の本体解明、新規バイオマーカーの同定やCAR-T療法などの細胞療法含む新規治療開発に繋がると考えている。

Report

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

    (4 results)

All 2024 2023

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment2024

    • Author(s)
      Zhou W, Kawashima S, Ishino T, Kawase K, Ueda Y, Yamashita K, Watanabe T, Kawazu M, Dansako H, Suzuki Y, Nishikawa H, Inozume T, Nagasaki J, Togashi Y.
    • Journal Title

      Cell Reports

      Volume: - Issue: 2 Pages: 113797-113797

    • DOI

      10.1016/j.celrep.2024.113797

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Immunologic Significance of CD80/CD86 or Major Histocompatibility Complex-II Expression in Thymic Epithelial Tumors2023

    • Author(s)
      Ikeda Hideki、Nagasaki Joji、Shimizu Daiki、Katsuya Yuki、Horinouchi Hidehito、Hosomi Yukio、Tanji Etsuko、Iwata Takekazu、Itami Makiko、Kawazu Masahito、Ohe Yuichiro、Suzuki Takuji、Togashi Yosuke
    • Journal Title

      JTO Clinical and Research Reports

      Volume: 4 Issue: 10 Pages: 100573-100573

    • DOI

      10.1016/j.jtocrr.2023.100573

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects2023

    • Author(s)
      Kawase K、Kawashima S、Nagasaki J、Inozume T、Tanji E、Kawazu M、Hanazawa T、Togashi Y
    • Journal Title

      Cancer Immunology Research

      Volume: In press Issue: 7 Pages: 895-908

    • DOI

      10.1158/2326-6066.cir-22-0815

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Presentation] CD4+ T cell exhaustion in the tumor microenvironment and antitumor immunity2024

    • Author(s)
      Joji Nagasaki, Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Takashi Inozume, and Yosuke Togashi
    • Organizer
      American association of cancer research
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research

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Published: 2022-09-01   Modified: 2025-01-30  

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