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Overcoming immunotherapy-resistant cancers by comprehensively screening sensitizing pathways

Research Project

Project/Area Number 22K20758
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0803:Pathology, infection/immunology, and related fields
Research InstitutionKyoto University

Principal Investigator

Ito Yoshinaga  京都大学, 医生物学研究所, 教授 (60614013)

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免疫療法抵抗性癌 / 免疫療法抵抗性がん / がん免疫療法 / 治療抵抗性がん / オートファジー / TNFシグナル経路 / T細胞 / 癌免疫療法 / 治療抵抗性癌
Outline of Research at the Start

免疫療法は他の治療が無効な癌患者にも長期寛解を導入可能で、癌治療の切り札になり得る。しかし半数以上で治療抵抗性となるため、抵抗性癌の克服が重要な課題である。抵抗性癌は感受性癌細胞から生じた少数の抵抗性細胞から始まる。申請者はこれまでに免疫治療抵抗性癌細胞を感受性化できる遺伝子標的を網羅的に同定した。本研究ではその分子機序を明らかにする。さらにその理解に基づいて抵抗性細胞を感受性化し、免疫感受性癌細胞に対するT細胞反応の周囲環境への波及効果を利用して、同一癌組織内の抵抗性癌細胞を少数のうちに殺傷することで、抵抗性癌の出現を防ぐ、という新規治療戦略を実証する。

Outline of Final Research Achievements

Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I)-bound peptides, but this selection pressure favors outgrowth of MHC-I-deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell-mediated killing of MHC-deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-deficient tumor cells to apoptosis by T cell-derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified proapoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I-deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFNγ- and TNFα-producing T cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では、治療抵抗性の原因の一つである腫瘍の不均一性に着目し、そこに含まれる抵抗性がん細胞のTNFシグナル経路とオートファジーを標的として不活性化することが、新たな治療戦略となりうることを示した。例えば、免疫チェックポイント阻害剤による治療を行う際に両経路に対する薬剤を併用すれば、MHC-I欠損がん細胞の増加による治療抵抗性がんの出現を抑えることができる可能性がある。

Report

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

    (11 results)

All 2024 2023 2022 Other

All Int'l Joint Research (1 results) Journal Article (3 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 3 results,  Open Access: 1 results) Presentation (2 results) Remarks (5 results)

  • [Int'l Joint Research] Dana-Farber Cancer Institute/Harvard Medical School/Broad Institute(米国)

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell?Secreted Cytokines2023

    • Author(s)
      Ito Yoshinaga、Pan Deng、Zhang Wubing、Zhang Xixi、Juan Tiffany Y.、Pyrdol Jason W.、Kyrysyuk Oleksandr、Doench John G.、Liu X. Shirley、Wucherpfennig Kai W.
    • Journal Title

      Cancer Discovery

      Volume: 13 Issue: 5 Pages: 1186-1209

    • DOI

      10.1158/2159-8290.cd-22-1125

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell-secreted Cytokines2023

    • Author(s)
      Yoshinaga Ito, Deng Pan, Wubing Zhang, Xixi Zhang, Tiffany Y Juan, Jason W Pyrdol, Oleksandr Kyrysyuk, John G Doench, X Shirley Liu, Kai W Wucherpfennig
    • Journal Title

      Cancer Discovery

      Volume: -

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease2022

    • Author(s)
      Tanaka Atsushi、Maeda Shinji、Nomura Takashi、Llamas-Covarrubias Mara Anais、Tanaka Satoshi、Jin Lin、Lim Ee Lyn、Morikawa Hiromasa、Kitagawa Yohko、Akizuki Shuji、Ito Yoshinaga、Fujimori Chihiro、Hirota Keiji、et al、Sakaguchi Shimon
    • Journal Title

      Journal of Experimental Medicine

      Volume: 220 Issue: 2 Pages: 1-5

    • DOI

      10.1084/jem.20220386

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell-Secreted Cytokines2024

    • Author(s)
      伊藤 能永
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell-Secreted Cytokines2023

    • Author(s)
      伊藤 能永
    • Organizer
      第97回日本薬理学会年会
    • Related Report
      2023 Annual Research Report
  • [Remarks] 主要論文

    • URL

      https://ito-lab.labby.jp/publication

    • Related Report
      2023 Annual Research Report
  • [Remarks] 難治性がんの新しい治療標的の解明:T細胞サイトカインに対して抵抗性がん細胞を感受性化する

    • URL

      https://www.infront.kyoto-u.ac.jp/post-3875/

    • Related Report
      2023 Annual Research Report
  • [Remarks] 難治性がんの新しい治療標的の解明-T細胞サイトカインに癌細胞を感受性化する-

    • URL

      https://www.kyoto-u.ac.jp/ja/research-news/2023-02-24-6

    • Related Report
      2023 Annual Research Report
  • [Remarks]

    • URL

      https://www.kyoto-u.ac.jp/ja/research-news/2023-02-24-6

    • Related Report
      2022 Research-status Report
  • [Remarks]

    • URL

      https://www.infront.kyoto-u.ac.jp/post-3875/

    • Related Report
      2022 Research-status Report

URL: 

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

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