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Searching for immune checkpoint molecules regulated by an RNA-binding protein HuR

Research Project

Project/Area Number 19K22533
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 InstitutionNara Institute of Science and Technology

Principal Investigator

KAWAI TARO  奈良先端科学技術大学院大学, 先端科学技術研究科, 教授 (50456935)

Project Period (FY) 2019-06-28 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords自然免疫 / 腫瘍 / 樹状細胞 / RNA結合タンパク質 / 抗腫瘍免疫 / 免疫逃避 / 腫瘍免疫 / RNA / サイトカイン
Outline of Research at the Start

がん細胞は免疫系で認識され排除される一方、免疫細胞の腫瘍内浸潤や活性化を抑制する機構を備えており免疫系からの攻撃を回避している。我々は、RNA結合タンパク質Hu antigen R (HuR; 別名ELAV1)を欠損させた肺がん細胞を移植したマウスでは、腫瘍免疫系が活性化している知見を得た。本研究では、HuR欠損がん細胞で発現が減少している遺伝子群の中から免疫抑制に関わると予想される細胞表面分子等を抽出し、それらを個々に欠損したLLC細胞を樹立し、マウスへと移植することで、その後の腫瘍免疫誘導を検討し、新たなチェックポイント分子の発見に繋げる。

Outline of Final Research Achievements

We focused on the immune evasion mechanism of cancer cells to search for new genes and to elucidate their mechanisms of action. We found that the infiltration of killer T cells into the tumor tissue was significantly increased and the tumor volume was decreased in mice transplanted with LLC cells lacking HuR, a mRNA-binding protein that medites its stability. By searching for HuR-target genes, we identified a chemokine CCL2. The lack of CCL2 suppressed the growth of tumor volume, and decreased macrophages and increased killer T cells in the tumor tissues, suggesting that LLC cells evade immune surveillance by increasing CCL2 expression via HuR.

Academic Significance and Societal Importance of the Research Achievements

今回、がんによる免疫逃避機構の一つとしてHuRを介したCCL2発現誘導が存在することが示唆された。本研究は抗腫瘍免疫応答の分子機構の一つを明らかにしたという学術的意義にとどまらず、HuRやCCL2が新たな免疫チェックポイント阻害剤の標的となり得ることを示唆している点で大きな社会的意義もある。

Report

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

    (13 results)

All 2021 2020 2019

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (3 results) (of which Int'l Joint Research: 1 results,  Invited: 3 results) Book (2 results)

  • [Journal Article] Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases2021

    • Author(s)
      Okude Haruna、Ori Daisuke、Kawai Taro
    • Journal Title

      Frontiers in Immunology

      Volume: 11 Pages: 1-19

    • DOI

      10.3389/fimmu.2020.625833

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Ca2+-dependent pathway contributes to changes in the subcellular localization and extracellular release of interleukin-332020

    • Author(s)
      Momota Masatoshi、Nagayama Mizuka、Okude Haruna、Ishii Ken J.、Ori Daisuke、Kawasaki Takumi、Kawai Taro
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 530 Issue: 4 Pages: 699-705

    • DOI

      10.1016/j.bbrc.2020.07.127

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of nucleoporin 93 (Nup93) that mediates antiviral innate immune responses2020

    • Author(s)
      Monwan Warunthorn、Kawasaki Takumi、Hasan Md Zobaer、Ori Daisuke、Kawai Taro
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 521 Issue: 4 Pages: 1077-1082

    • DOI

      10.1016/j.bbrc.2019.11.035

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Innate immune responses through Toll-like receptor 3 require human-antigen-R-mediated Atp6v0d2 mRNA stabilization2019

    • Author(s)
      Zainol Mohd Izwan Bin、Kawasaki Takumi、Monwan Warunthorn、Murase Motoya、Sueyoshi Takuya、Kawai Taro
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 20406-20406

    • DOI

      10.1038/s41598-019-56914-w

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Cytosolic Sensor, PmDDX41, Binds Double Stranded-DNA and Triggers the Activation of an Innate Antiviral Response in the Shrimp Penaeus monodon via the STING-Dependent Signaling Pathway.2019

    • Author(s)
      Soponpong S, Amparyup P, Kawai T, Tassanakajon A.
    • Journal Title

      Front Immunol.

      Volume: 10 Pages: 2069-2069

    • DOI

      10.3389/fimmu.2019.02069

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genome organization and definition of the Penaeus monodon viral responsive protein 15 (PmVRP15) promoter.2019

    • Author(s)
      Jaree P, Kawai T, Lo CF, Tassanakajon A, Somboonwiwat K.
    • Journal Title

      Fish Shellfish Immunol.

      Volume: 93 Pages: 997-1006

    • DOI

      10.1016/j.fsi.2019.08.026

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Penaeus monodon IKKs Participate in Regulation of Cytokine-Like System and Antiviral Responses of Innate Immune System.2019

    • Author(s)
      Nhnhkorn Z, Amparyup P, Kawai T, Tassanakajon A.
    • Journal Title

      Front Immunol.

      Volume: 10 Pages: 1430-1430

    • DOI

      10.3389/fimmu.2019.01430

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] PtdIns3P phosphatases MTMR3 and MTMR4 negatively regulate innate immune responses to DNA through modulating STING trafficking2019

    • Author(s)
      Putri DDP, Kawasaki T, Murase M, Sueyoshi T, Deguchi T, Ori D, Suetsugu S, Kawai T.
    • Journal Title

      J Biol Chem

      Volume: - Issue: 21 Pages: 8412-8423

    • DOI

      10.1074/jbc.ra118.005731

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Local expansion of CD8+ T cells by tissue resident macrophages in the lung2019

    • Author(s)
      Kawai T, Kawasaki T
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] The role of innate immune signaling pathways in induction of anti-cancer immunity2019

    • Author(s)
      Kawai T
    • Organizer
      The 6th ICPAPS-The 3rd ASEAN PharmNET 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 自然免疫による病原体や内在性因子の認識と炎症制御のメカニズムについて2019

    • Author(s)
      河合太郎
    • Organizer
      免疫サマースクール2019
    • Related Report
      2019 Research-status Report
    • Invited
  • [Book] 日本医師会雑誌特別号免疫・炎症疾患の基礎知識2020

    • Author(s)
      百田匡寿、河合太郎
    • Total Pages
      367
    • Publisher
      (公社)日本医師会
    • Related Report
      2020 Annual Research Report
  • [Book] 免疫・炎症病態×治療Update2019

    • Author(s)
      加納規資、織大祐、河合太郎
    • Total Pages
      252
    • Publisher
      南山堂
    • ISBN
      9784525167813
    • Related Report
      2019 Research-status Report

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Published: 2019-07-04   Modified: 2022-01-27  

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