Overcoming resistance to immune checkpoint inhibitors in KRAS-LKB1 mutant lung cancer.
| Project/Area Number |
20H03521
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Japanese Foundation for Cancer Research |
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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)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| 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)
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| Keywords | 非小細胞肺がん / KRAS / STING / STK11 / LKB1 |
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| 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。
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| 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.
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| 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。
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Report
(4 results)
Research Products
(11 results)
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[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.
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Journal Title
Frontiers in Immunology
Volume: 11
Pages: 2090-2090
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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