2023 Fiscal Year Final Research Report

Development of irAE management strategy based on immuno-senescence, and novel cancer immunotherapy balancing augmented anti-tumor immunity and decreased risk of adverse events

Research Project

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Project/Area Number	21H02788
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 50020:Tumor diagnostics and therapeutics-related
Research Institution	Kyoto University
Principal Investigator	Tsukamoto Hirotake 京都大学, 医学研究科, 特定准教授 (10433020)
Co-Investigator(Kenkyū-buntansha)	池田徳典崇城大学, 薬学部, 准教授 (00613530) 冨田雄介熊本大学, 大学院生命科学研究部(医), 助教 (90648619)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	がん免疫療法 / 免疫関連有害事象 / T細胞 / 個体老化
Outline of Final Research Achievements	To establish cancer immunotherapy as an effective and safe treatment, it is essential to elucidate the pathogenesis of immune-related adverse events (irAE). In this research project, we found that anti-PD-(L)1 therapy induced the formation of tertiary lymphoid tissue-like structures with ectopic infiltration of T and B cells, antibody deposition, and organ damages in the lung, liver, and kidney of tumor-bearing aged mice. These research findings, and related pre-clinical study has been published as two scientific literatures. Therefore, we utilized this experimental system as novel experimental animal model for anti-PD-(L)1 therapy-induced irAEs. Furthermore, we found that anti-PD-1 therapy induced CD4 T cells with a certain characteristic trait in damaged lung of tumor-bearing aged mice, and that this population could be a candidate biomarker for predicting the development of irAE symptom including pneumonitis.
Free Research Field	腫瘍免疫学
Academic Significance and Societal Importance of the Research Achievements	PD-1阻害療法に伴うirAE発症の実験マウスモデル、さらにPD-1阻害療法を受けたがん患者検体を用いた解析にて得られた本研究の成果は、がん免疫療法に伴うirAE発症機序の一端を明らかにした、という学術的意義を有する。さらに本研究にて得られた知見は、irAE発症の予測、鑑別を可能にするバイオマーカーとして応用できる、という有望性があり、さらなる普及が見込まれるがん免疫療法において、より安全性の高い治療選択への発展に大きく寄与するものと考えられる。今後は、がんを攻撃する免疫応答の増強と、irAE症状を軽減、改善するマネジメント戦略の両立の実装を目指し、さらなる研究を進める必要がある。