Overcoming immunotherapy-resistant cancers by comprehensively screening sensitizing pathways

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K20758
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0803:Pathology, infection/immunology, and related fields
• Research Institution: Kyoto University
• Principal Investigator: Ito Yoshinaga 京都大学, 医生物学研究所, 教授 (60614013)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Keywords: 免疫療法抵抗性癌

Outline of Final Research Achievements

Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I)-bound peptides, but this selection pressure favors outgrowth of MHC-I-deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell-mediated killing of MHC-deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-deficient tumor cells to apoptosis by T cell-derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified proapoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I-deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFNγ- and TNFα-producing T cells.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究では、治療抵抗性の原因の一つである腫瘍の不均一性に着目し、そこに含まれる抵抗性がん細胞のTNFシグナル経路とオートファジーを標的として不活性化することが、新たな治療戦略となりうることを示した。例えば、免疫チェックポイント阻害剤による治療を行う際に両経路に対する薬剤を併用すれば、MHC-I欠損がん細胞の増加による治療抵抗性がんの出現を抑えることができる可能性がある。