anti tumor immunology against GIST through immunecheckpoint mechnism

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09292
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Jikei University School of Medicine
• Principal Investigator: KOMITA HIDEO 東京慈恵会医科大学, 医学部, 助教 (90534561)
• Co-Investigator(Kenkyū-buntansha): 本間 定 東京慈恵会医科大学, 医学部, 教授 (50192323)
• Project Period (FY): 2016-04-01 – 2019-03-31
• 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

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.

Free Research Field

腫瘍免疫学

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