biostudies-literatureIto YJapan Society for the Promotion of Science LondonBasic Research LaboratoryKyoto University FoundationNCI NIH HHS1186-1209https://www.ebi.ac.uk/biostudies/studies/S-EPMC10164097biostudies-literatureUnknown13(5)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-I-deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-I-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-presenCancer discoveryAddressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell-Secreted Cytokines.PMC10164097P01 CA16322222K20758P30 CA006516R01 CA238039P01 CA236749R01 CA234018R01 CA251599Zhang WJuan TYKyrysyuk OWucherpfennig KWPan DIto YZhang XDoench JGPyrdol JWLiu XSfalseAddressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell-Secreted Cytokines.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-I-deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-I-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-presen2023-01-01T00:00:00Z2023 May2025-04-04T03:01:11.209Z2025-04-04T03:01:11.209ZS-EPMC101640973681146610.1158/2159-8290.CD-22-112510.1158/2159-8290.cd-22-1125