| Project/Area Number |
16K07181
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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 |
Tumor therapeutics
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| Research Institution | Keio University |
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Principal Investigator |
Tsukamoto Nobuo 慶應義塾大学, 医学部(信濃町), 助教 (20407117)
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| Co-Investigator(Kenkyū-buntansha) |
河上 裕 慶應義塾大学, 医学部(信濃町), 教授 (50161287)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 腫瘍免疫 / がん免疫治療 / 免疫抑制 / IDO / TDO / AhR / IDO1 / TDO2 / がん微小環境 |
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| Outline of Final Research Achievements |
Tumor tissues are inhomogeneous and various immune-suppressive mechanisms suppress anti-tumor immunity. We identified a novel mechanism of immunosuppression through downstream molecules of Aryl hydrocarbon receptor (AhR) in cancer cells in tumor microenvironments and identified several molecules responsible for this immunosuppression observed in tumor with activated IDO-kynurenine-AhR pathway. We also found that IDO is phosphorylated in human cancer tissues, and we identified a kinase responsible for phosphorylation of one of the IDO phosphorylation sites. We also identified mutations which decreases protein expression of IDO in cancer cells and clarified part of mechanisms of the phenomena. Furthermore, we identified drugs which can suppress transcription of IDO1 in cancer cells. We further tried analysis of tumor microenvironment under the hypoxia condition.
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| Academic Significance and Societal Importance of the Research Achievements |
近年、抗CTLA-4抗体や抗PD-1抗体投与、がん抗原特異的T細胞を投与する免疫療法の臨床試験においてがん患者の長期生存につながる明確な治療効果が認められているが、これらが効かない症例では、がん微小環境の免疫抑制病態が大きな原因とされている。特にがん患者のがん組織は非常に不均一であり多様な免疫抑制機構が存在することが免疫抑制の解除を困難にしている。本研究の結果は、がん組織における不均一で多様な免疫抑制機構の分子細胞機構の解明と改善法の開発に重要な手がかりを与えるものであり、免疫療法、さらには標準治療の改善にもつながると期待される。
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