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Reprogramming of exhausted CTL by targeting enhancers with multi-dimensional regulatory activities

Research Project

Project/Area Number 21H02756
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49070:Immunology-related
Research InstitutionNational Center for Global Health and Medicine

Principal Investigator

Sekiya Takashi  国立研究開発法人国立国際医療研究センター, その他部局等, 免疫応答修飾研究室長 (80519207)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2023: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Keywords免疫学 / 抗腫瘍免疫 / 細胞リプログラミング / エピジェネティクス / 癌免疫 / ゲノム編集 / 腫瘍免疫
Outline of Research at the Start

「免疫チェックポイント阻害剤(immune checkpoint blockade; ICB)」による抗腫瘍免疫の賦活化は、様々な進行癌の治療を可能とした。一方で奏効率や、対象となる癌種は依然限られている。従って、腫瘍組織で細胞傷害性T細胞(CTL)の疲弊化が誘導されるメカニズムのさらなる理解や、疲弊化CTLの賦活化を高効率かつ持続的に誘導する新規手法の開発は重要な課題である。本研究は、申請者が先行研究で構築した「新規・転写制御領域gRNAライブラリ」を基盤としたスクリーニングにより、疲弊化CTLに賦活化リプログラミングを導くエピジェネティック操作法の開発を目指す。

Outline of Final Research Achievements

In this study, we aimed to develop a reprogramming method for activating exhausted CTLs by epigenetic modification, and first created a gRNA library for the transcriptional control region of exhausted CTLs and activated CTLs. Furthermore, we created exhausted CTL reporter cell lines and used these gRNA libraries and reporter cell lines to screen for gene regions and epigenetic manipulations that activate exhausted CTL. As a result, we identified the genetic region and epigenetic manipulation that lead to decreased expression of PD-1 in exhausted CTLs. Gene expression analysis confirmed that the epigenetic manipulation reprograms exhausted CTLs into cells with properties similar to activated CD8T cells.

Academic Significance and Societal Importance of the Research Achievements

抗腫瘍免疫の賦活化は、様々な進行癌の治療を可能としたが、細胞傷害性T細胞(CTL)の疲弊化が引き起こされるメカニズムの理解や、疲弊化CTLの賦活化を誘導する手法の開発は、重要な研究課題であった。本研究で開発した「転写制御領域gRNAライブラリ」によるスクリーニングでは、既知の領域ではあったが、疲弊化CTLの賦活化を導く遺伝子領域、エピジェネティック操作法を見出すことに成功した。このことは、さらなるライブラリのスケールアップ及びスクリーニングの継続で、新規遺伝子領域およびエピジェネティック操作法を見出せる可能性を示しており、また、様々な細胞リプログラミングの試みに手掛かりを与えると期待できる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (7 results)

All 2024 2023 2022 2021

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (2 results) (of which Invited: 1 results) Book (1 results)

  • [Journal Article] Tonic TCR and IL-1β signaling mediate phenotypic alterations of naive CD4+ T?cells2024

    • Author(s)
      Sekiya Takashi、Hidano Shinya、Takaki Satoshi
    • Journal Title

      Cell Reports

      Volume: 43 Issue: 3 Pages: 113954-113954

    • DOI

      10.1016/j.celrep.2024.113954

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Estimation of Sensitization Status in Renal Transplant Recipients by Assessing Indirect Pathway CD4+ T Cell Response to Donor Cell-pulsed Dendritic Cell2023

    • Author(s)
      Kenta Iwasaki、Toshihide Tomosugi、Takashi Sekiya、Shintaro Sakamoto、Yuko Miwa、Manabu Okada、Takahisa Hiramitsu、Norihiko Goto、Shunji Narumi、Yoshihiko Watarai、Mai Okumura、Satoshi Ashimine、Kohei Ishiyama、Ezzelarab Mohamed B.、Takaaki Kobayashi
    • Journal Title

      Transplantation

      Volume: 107 Issue: 5 Pages: 1079-1088

    • DOI

      10.1097/tp.0000000000004491

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Comparison between Nr4a transcription factor regulation and function in lymphoid and tumor Treg cells2022

    • Author(s)
      Takashi Sekiya
    • Journal Title

      Frontiers in Immunology

      Volume: in press Pages: 866339-866339

    • DOI

      10.3389/fimmu.2022.866339

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [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 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 免疫抑制剤存在下でのTreg分化における転写因子NR4A1の役割2023

    • Author(s)
      関谷 高史
    • Organizer
      第20回 日本免疫治療学会学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Tonic TCR and IL-1b signaling mediate momentary and durable phenotypic alterations in naive CD4+ T cells2022

    • Author(s)
      関谷 高史
    • Organizer
      第51回 日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Book] Nr4aによるTh/Tregのバランス制御と炎症性疾患2021

    • Author(s)
      関谷 高史
    • Total Pages
      4
    • Publisher
      先端医学社
    • Related Report
      2021 Annual Research Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

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