Mechanism of resistance to immune checkpoint inhibitors in a novel tumor-bearing dermal immune-related adverse event model mouse

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15617
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kurashiki University of Science and the Arts (2023); Foundation for Biomedical Research and Innovation at Kobe (2022)
• Principal Investigator: Keiichiro Mie 倉敷芸術科学大学, 生命科学部, 講師 (30791082)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 免疫チェックポイント阻害薬 / 免疫関連有害事象 / PD-1 / CD8陽性T細胞

Outline of Final Research Achievements

Immune checkpoint inhibitors (ICIs) including anti-PD-1 antibody dramatically improved treatment of tumor patients including who are not responding well to conventional anti-tumor treatments; however, a significant fraction of patients is unresponsive to ICIs even if the type of tumor seems to be responsive to ICIs. In this study, it was revealed that anti-tumor effect of anti-PD-L1 antibody significantly correlated with the degree of immune-related adverse event (irAE) in a novel tumoe-bearing dermal irAE model mouse. It was suggested that he mechanism of the correlation might be the inhibition of PI3K/AKT/mTOR pathway of CD8+ T cells by the tumor rather than be the inhibition of T cell receptor (TCR) signal transduction.

Free Research Field

獣医学

Academic Significance and Societal Importance of the Research Achievements

本研究では、実臨床におけるICIsの抗腫瘍効果とirAE発症が相関する現象を再現するモデルマウスの作製に成功し、その機序は腫瘍によるCD8陽性T細胞のPI3K/AKT/mTOR経路の阻害であることが示唆された。抗腫瘍効果とirAE発症はそれぞれ別の抗原を認識するCD8陽性エフェクターT細胞であること、および本研究で使用したマウスや株化腫瘍細胞の遺伝的背景は同一であることから、この機序は遺伝的背景や抗原の種類に影響されず、かつ腫瘍の微小環境にも非依存的な全身性の免疫抑制機序であると推測され、実臨床におけるICIsに対する腫瘍の耐性獲得機序の解明につながりうる知見であると考えられる