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Overcoming resistance to immune checkpoint inhibitors in KRAS-LKB1 mutant lung cancer.

Research Project

Project/Area Number 20H03521
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionJapanese Foundation for Cancer Research

Principal Investigator

KITAJIMA Shunsuke  公益財団法人がん研究会, がん研究所 細胞生物部, 研究員 (90566465)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2020: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords非小細胞肺がん / KRAS / STING / STK11 / LKB1
Outline of Research at the Start

PD-1阻害薬に対して治療抵抗性を示すKRAS;LKB1変異型非小細胞がんに対して、STING経路活性化を介して免疫チェックポイト阻害剤抵抗性を克服するための新規治療法を開発する。KRAS;LKB1変異型非小細胞がんが示すSTINGアゴニストの低い膜透過性、STINGの低発現という2つの問題を克服するため、細胞内在性STINGアゴニストであるcGAMPの産生亢進およびSTINGの発現亢進を誘導する薬剤の探索を行う。さらに、KL型NSCLC患者で観察される腫瘍内浸潤リンパ球の割合が低い免疫微小環境形成の分子基盤を、血管ネットワークおよびがん細胞スフェロイドの共培養システムを用いて解析する。

Outline of Final Research Achievements

Previously, we reported that KRAS-LKB1 mutant (KL) non-small cell lung cancer (NSCLC), which is resistant to immune checkpoint inhibitors, shows marked silencing of STING, an adaptor protein that links cytoplasmic dsDNA accumulation to activation of downstream innate immune signaling. STING downstream cytokines are key molecules for T-cell recruitment into the tumor microenvironment (TME), and indeed, infiltration of T-cells into the TME is significantly lower in KL-type NSCLC. Through an unbiased screen of cytotoxic chemotherapies or targeted DNA-damaging agents for their ability to induce STING activation, we identified MPS1 inhibitor as an optimal agent to prime the STING pathway in KL cells via micronuclei creation. We also found that STING-dependent infiltration of CD8-positive T cells following treatment with MPS1 inhibitor was required for long-term efficacy to MPS1 inhibitor in a syngeneic murine KL-type NSCLC model.

Academic Significance and Societal Importance of the Research Achievements

日本国内における肺癌の死亡率は男性で第1位、女性で第2位となっており、年間7万人以上の人々が肺がんで亡くなっている。免疫チェックポイント阻害薬(ICI)は、がん治療に革命をもたらし、現在の肺がん薬物治療の根幹を成しているが、一部のがん患者にしか奏功しない。ICI治療抵抗性を示す代表的ながん種であるKRAS-LKB1変異型非小細胞肺がんをモデルとして、がん組織の免疫原性が低下する分子機序を理解し、その成果に基づきICI治療抵抗性の克服を目指す。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (11 results)

All 2022 2021 2020 Other

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

  • [Int'l Joint Research] Dana-Farber Cancer Institute(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Dana-Farber Cancer Institute(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Dana-Farber Cancer Institute(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer2022

    • Author(s)
      Kitajima Shunsuke、Tani Tetsuo、Springer Benjamin F.、Campisi Marco、Osaki Tatsuya、Haratani Koji、Chen Minyue、Knelson Erik H.、Mahadevan Navin R.、Ritter Jessica、Yoshida Ryohei、Kohler Jens、Ogino Atsuko、Nozawa Ryu-Suke、他14名
    • Journal Title

      Cancer Cell

      Volume: 40 Issue: 10 Pages: 1128-1144

    • DOI

      10.1016/j.ccell.2022.08.015

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] KRAS G12C inhibition and innate immune targeting2021

    • Author(s)
      T.Tani, S.Kitajima, EB.Conway, EH.Knelson, and DA. Barbie
    • Journal Title

      Expert Opinion on Therapeutic Targets

      Volume: - Issue: 3 Pages: 167-174

    • DOI

      10.1080/14728222.2021.1902991

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Tumor-Derived cGAMP Regulates Activation of the Vasculature2020

    • Author(s)
      Campisi Marco, Sundararaman Shriram K.、Shelton Sarah E., Ryohei,Tani Tetsuo、Ivanova Elena, Osaki Tatsuya, Lee Sharon Wei Ling, Thai Tran, Han Saemi、Piel Brandon P., Gilhooley Sean, Paweletz Cloud P.,Chiono Valeria、Kamm Roger D., Kitajima Shunsuke、Barbie David A.
    • Journal Title

      Frontiers in Immunology

      Volume: 11 Pages: 2090-2090

    • DOI

      10.3389/fimmu.2020.02090

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer2022

    • Author(s)
      北嶋俊輔
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 1.Novel strategy for priming immunogenicity of KRAS;LKB1 mutant lung cancer through MPS1 inhibition2021

    • Author(s)
      北嶋俊輔
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 2.紡錘体チェックポイントキナーゼMPS1によるSTING経路の制御機構解明とがん免疫療法への応用2021

    • Author(s)
      北嶋俊輔
    • Organizer
      第94回日本生化学大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 1.Novel strategy for priming immunogenicity of KRAS;LKB1 mutant lung cancer through MPS1 inhibition2021

    • Author(s)
      北嶋俊輔
    • Organizer
      第62回日本肺癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] MPS1阻害剤を用いたKRAS/LKB1変異型肺がんが示す免疫チェックポイント阻害薬2020

    • Author(s)
      北嶋俊輔
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
    • Invited

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Published: 2020-04-28   Modified: 2024-01-30  

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