| Project/Area Number |
16K09292
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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 |
Gastroenterology
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| Research Institution | Jikei University School of Medicine |
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Principal Investigator |
KOMITA HIDEO 東京慈恵会医科大学, 医学部, 助教 (90534561)
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| Co-Investigator(Kenkyū-buntansha) |
本間 定 東京慈恵会医科大学, 医学部, 教授 (50192323)
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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 |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | GIST / Tim-3 / Galectin-9 / Imatinib / WT1 / NK cell / CD8+T cell / 免疫チェックポイント阻害剤 / 初代培養 / 腫瘍浸潤単核球 / 抗腫瘍免疫 / 免疫チェックポイント / PD-L1 / NK細胞 / PD-1 / 細胞障害性T細胞 |
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| Outline of Final Research Achievements |
Abundant mononuclear cells were migrated from the tumor tissue fragments of human gastric gastrointestinal stromal tumor (GIST) in primary culture. Addition of interleukin-2 into the culture provided vigorous tumor cell killing by the mononuclear cells in vitro, indicating that cytotoxic immune cells were infiltrated in the GIST tissue. Immuno-histochemical analysis of human gastric GIST tissue demonstrated that Tim-3/galectin-9 axis might be the immune checkpoint mechanism that suppresses NK cell activity. Imatinib treatment of GIST-T1 cells showed downregulation of galectin-9 protein expression. Imatinib also suppressed interferon-gamma-induced upregulation of PD-L1. However, imatinib treatment enhanced prostaglandin E2 production and suppressed WT1 expression in GIST-T1 cells. Imatinib treatment may elicit both promotive and suppressive effects on antitumor immune activity against GIST.
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| Academic Significance and Societal Importance of the Research Achievements |
GISTに対する免疫チェックポイント機構に関連した研究は現在まで極めて少数に限られていたが、本研究によりGISTの免疫チェックポイント機構はTim-3/galectin-9によるNK細胞の抑制であることを示す成果が初めて得られた。このことから、進行したGIST症例に対してはTim-3抗体を用いた免疫チェックポイント阻害療法が有効である可能性が示された
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