Analysis of resistant mechanism for immune check point inhibitor using original mice model

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09160
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Gunma University
• Principal Investigator: Kawatani Natsuko 群馬大学, 医学部附属病院, 助教 (80805557)
• Co-Investigator(Kenkyū-buntansha): 矢島 俊樹 群馬大学, 大学院医学系研究科, 准教授 (20346852) ; 大瀧 容一 群馬大学, 医学部附属病院, 助教 (00625402) ; 中澤 世識 群馬大学, 医学部附属病院, 助教 (60791978)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 耐性機序 / 疲弊化CD8T細胞 / TIGIT

Outline of Final Research Achievements

To examine the dynamics of the several immune chock point molecules on antigen-specific CD8+ T cells during tumor immune response, we originally developed useful mice model using OT-I mice. We found that PD-1 expressions were detected on almost all OT-I cells, whereas the expression of the other molecules including TIGIT, TIM-3, LAG-3, or CTLA-4 were partly detected on those cells indicating that generated OT-I cells were heterogenous population. TIGIT expression were upregulated on OT-I cells by anti-PD-1 mAb treatment resulting abrogated tumor growth suppression. On the other hand, substantial OT-I activation were found by anti-PD-1 mAb treatment adding anti-TIGIT treatment resulting showed substantial tumor growth suppression. These results suggested that TIGIT upregulation on OT-I cells were resistant mechanism for anti-PD-1 mAb treatment.

Free Research Field

Cancer immune therapy

Academic Significance and Societal Importance of the Research Achievements

近年、PD-1/PD-L1シグナルをブロックし疲弊化CD8T細胞を再活性化させる癌免疫療法が臨床応用され注目を集めているが、その効果は限定的であり、耐性メカニズムを明らかにすることが必要である。本研究では抗原特異的CD8T細胞における免疫チェックポイント分子の動態を解析することにより、PD-1抗体治療の耐性メカニズムとしてTIGITが関与していることを明らかにすることができた。抗PD-1抗体治療に加えて抗TIGIT抗体を併用することにより、この耐性は解除され新規癌免疫療法の開発への可能性を見出すことができたため臨床応用への可能性が期待できる研究となった。