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Regulatory mechanisms of anti-tumor immunity by inhibitory coreceptor, LAG-3

Research Project

Project/Area Number 19K16694
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 49070:Immunology-related
Research InstitutionThe University of Tokyo

Principal Investigator

Maruhashi Takumi  東京大学, 定量生命科学研究所, 助教 (60743961)

Project Period (FY) 2019-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords免疫チェックポイント分子 / LAG-3 / がん免疫 / ヘルパーT細胞
Outline of Research at the Start

免疫チェックポイント阻害剤の抗腫瘍効果が証明されて以降、がん免疫療法は大きな注目を集めている。しかしながら、その奏功率は30%程度と決して高いとは言えず、依然として解決すべき課題が多く残されている。本研究では、CD4陽性ヘルパーT細胞(Th細胞)および抑制性免疫補助受容体LAG-3に焦点を当て、がん免疫におけるTh細胞活性化制御機構の解析、そしてTh細胞の活性化制御による新規がん免疫療法の開発を目指す。本研究を通して、がん細胞がLAG-3を介して免疫監視を回避する新たなメカニズムが明らかになる可能性があるとともに、効果的な新規がん免疫療法の確立につながることが期待される。

Outline of Final Research Achievements

Lymphocyte activation gene-3 (LAG-3), one of the immune checkpoint molecules, expected as the foremost target next to PD-1 and CTLA-4 in the development of cancer immunotherapy. In this study, I investigated the involvement of LAG-3 in the regulation of immune responses against cancer and tried to elucidate the underlying mechanism.
Genetic deletion of LAG-3 exhibited therapeutic effects against tumor growth in several mouse models, which was accompanied by elevated cytokine production from tumor-infiltrating CD4-positive helper T (Th) cells. These results strongly suggest that LAG-3 contributes to immune escape mechanisms in tumors by regulating the activation of tumor-specific Th cells.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、ヘルパーT細胞による免疫監視機構およびがん細胞がLAG-3を介してその監視機構を回避する新たなメカニズムの一端を明らかにしたものである。また、LAG-3を標的としたヘルパーT細胞活性化制御法、そしてヘルパーT細胞を介したがん免疫応答賦活化という、今までに無い視点のがん免疫療法の開発につながる可能性があり、既存のがん免疫療法に抵抗性のがん腫、患者においても効果を示す可能性があるだけでなく、既存のがん免疫療法と併用することで奏効率の大幅な向上につながることが期待される。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (10 results)

All 2020 2019

All Journal Article (8 results) (of which Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (2 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] LAG-3: from molecular functions to clinical applications2020

    • Author(s)
      Maruhashi Takumi、Sugiura Daisuke、Okazaki Il-mi、Okazaki Taku
    • Journal Title

      Journal for ImmunoTherapy of Cancer

      Volume: 8 Issue: 2 Pages: e001014-e001014

    • DOI

      10.1136/jitc-2020-001014

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] PD-1 Imposes Qualitative Control of Cellular Transcriptomes in Response to T Cell Activation2020

    • Author(s)
      Shimizu Kenji、Sugiura Daisuke、Okazaki Il-mi、Maruhashi Takumi、Takegami Yujiro、Cheng Chaoyang、Ozaki Soichi、Okazaki Taku
    • Journal Title

      Molecular Cell

      Volume: 77 Issue: 5 Pages: 937-950

    • DOI

      10.1016/j.molcel.2019.12.012

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells2019

    • Author(s)
      Maeda Natsumi、Maruhashi Takumi、Sugiura Daisuke、Shimizu Kenji、Okazaki Il-mi、Okazaki Taku
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Issue: 52 Pages: 19896-19906

    • DOI

      10.1074/jbc.ra119.010379

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions2019

    • Author(s)
      Okamura Hikari、Okazaki Il-mi、Shimizu Kenji、Maruhashi Takumi、Sugiura Daisuke、Mizuno Reina、Okazaki Taku
    • Journal Title

      Journal of Autoimmunity

      Volume: 105 Pages: 102296-102296

    • DOI

      10.1016/j.jaut.2019.06.007

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] PD-1 Primarily Targets TCR Signal in the Inhibition of Functional T Cell Activation2019

    • Author(s)
      Mizuno Reina、Sugiura Daisuke、Shimizu Kenji、Maruhashi Takumi、Watada Mizuki、Okazaki Il-mi、Okazaki Taku
    • Journal Title

      Frontiers in Immunology

      Volume: 10 Pages: 630-630

    • DOI

      10.3389/fimmu.2019.00630

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses2019

    • Author(s)
      Sugiura Daisuke、Maruhashi Takumi、Okazaki Il-mi、Shimizu Kenji、Maeda Takeo K.、Takemoto Tatsuya、Okazaki Taku
    • Journal Title

      Science

      Volume: 364 Issue: 6440 Pages: 558-566

    • DOI

      10.1126/science.aav7062

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] PD-1 efficiently inhibits T cell activation even in the presence of co-stimulation through CD27 and GITR2019

    • Author(s)
      Mizuno Reina、Maruhashi Takumi、Sugiura Daisuke、Shimizu Kenji、Watada Mizuki、Okazaki Il-mi、Okazaki Taku
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 511 Issue: 3 Pages: 491-497

    • DOI

      10.1016/j.bbrc.2019.02.004

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation2019

    • Author(s)
      Maeda Takeo K.、Sugiura Daisuke、Okazaki Il-mi、Maruhashi Takumi、Okazaki Taku
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Issue: 15 Pages: 6017-6026

    • DOI

      10.1074/jbc.ra119.007455

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] LAG-3 inhibits the activation of CD4+ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII2019

    • Author(s)
      Takumi Maruhashi, Il-mi Okazaki, Daisuke Sugiura, Suzuka Takahashi, Takeo K. Maeda, Kenji Shimizu, Taku Okazaki
    • Organizer
      The 14th International Symposium of the Institute Network for Biomedical Sciences 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Binding properties between LAG-3 and two potential ligands, stable pMHCII and FGL12019

    • Author(s)
      Takumi Maruhashi, Jun Ikubo, Daisuke Sugiura, Il-mi Okazaki, Taku Okazaki
    • Organizer
      第48回日本免疫学会学術集会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-12-25  

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