Investigation of exhaustion-inducing factors and the mechanisms of exhaustion in canine chimeric antigen receptor T cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15018
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 42020:Veterinary medical science-related
• Research Institution: Azabu University
• Principal Investigator: Yoshimoto Sho 麻布大学, 獣医学部, 学振研究員 (70909168)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: CAR-T細胞 / T細胞の疲弊 / 免疫チェックポイント分子 / PD-1/PD-L1 / がん免疫 / がん / イヌ

Outline of Final Research Achievements

The aim of this study was to elucidate the mechanisms of CAR-T cell exhaustion, which reduces the therapeutic efficacy of CAR-T cell therapy. To induce CAR-T cell exhaustion, canine CAR-T cells were repeatedly stimulated with target antigens, and the process leading to exhaustion was evaluated. Our study revealed that canine CAR-T cells expressed exhaustion-related markers, accompanied by a gradual decline in their proliferation and cytotoxic abilities, ultimately resulting in functional impairment. Additionally, it was found that PD-L1-expressing cells contribute to the dysfunction of canine CAR-T cells and that PD-1 signal inhibition alleviates the suppression of CAR-T cell function caused by PD-L1. These findings provide insights into the mechanisms of canine CAR-T cell exhaustion.

Free Research Field

がん免疫

Academic Significance and Societal Importance of the Research Achievements

本研究の学術的意義は、イヌCAR-T細胞の疲弊の誘導に成功し、免疫チェックポイント分子の発現変化や機能不全に陥るまでの過程を明らかにしたことである。また、PD-1シグナル阻害がイヌCAR-T細胞の機能不全や疲弊に与える影響についても明らかにできた。これらは、CAR-T細胞療法の改善策を検討するための重要な知見である。社会的意義としては、CAR-T細胞の疲弊を防ぐ新たな戦略を提示したことで、イヌおよびヒトのがん患者に対するCAR-T細胞の治療効果の向上が期待されることである。特に、難治性がんの治療において、CAR-T細胞療法の適用範囲を拡大し、治療効果を最大化するための手がかりとなる研究である。