| Project/Area Number |
17K09652
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
寺本 晃治 滋賀医科大学, 医学部, 特任講師 (10452244)
醍醐 弥太郎 滋賀医科大学, 医学部, 教授 (30345029)
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | EGFRシグナル / ケモカイン / 免疫逃避 / MAPKシグナル / MAPK / EGFR / 肺癌 / Tリンパ球 / Trm細胞 / 免疫療法 |
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| Outline of Final Research Achievements |
We analyzed an immune evasion mechanism of EGFR-mutated (mt) lung adenocarcinoma (LA), focusing on the decrease of tumor-infiltrating T lymphocytes. Several chemokine mRNA expressions were decreased in EGFR-mt LA. We showed IFN-responsive Th1-recruiting chemokines, CXCL9, 10, and 11, were significantly suppressed under an EGFR signaling from the experiments using EGFR-mt cell lines. We analyzed the suppression mechanism of CXCL10, which is especially important for the recruitment of activated T cells. The presence of common enhancer regions regulating the gene cluster encompassing CXCL9, 10, and 11, was suggested, which might be regulated by EGFR signal-mediated epigenetic silencing.
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| Academic Significance and Societal Importance of the Research Achievements |
免疫チェックポイント阻害剤によるがん免疫療法はがん治療を大きく変えるインパクトをもたらしたが、まだ全てのがんに有効では無く治療耐性機構の解明とその克服が重要な課題である。EGFR変異肺腺癌は日本人の肺腺癌の約半数を占め、免疫チェックポイント阻害剤に耐性であることが判明しているがその機序はまだ十分に解明されていない。今回、EGFRシグナルによる耐性機構としてエピジェネティックなケモカイン阻害機構を示すことができた。薬剤によるその克服の可能性が考えられ、治療耐性を克服する新たな技術基盤に発展する可能性が考えられる。
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