Abstract 2154: Immune pressure selects ANKRD52 mutations for cancer cells to escape T cell-mediated killing

Cancer arises after somatic mutations override cellular and immunological control of cell proliferation. Mutations in oncogenes and tumor suppressor genes endow cancer cells intrinsic growth advantage over neighboring cells. Mutations can also enable cancer cells to survive immune clearance during cancer progression, but systematic analysis of such mutations is lacking. We hypothesized that some genetic alterations carried in cancer cell lines might specifically affect the cell fitness to T cell-mediated killing. By deep sequencing of syngeneic xenograft tumors receiving different levels of immune pressure, we enriched 53 mutations in clonal populations against T cell immunity. To differentiate the driver from passenger mutations, we performed in vivo and T cell co-culture CRISPR screens with a guide RNA library targeting these candidate genes. We identified ANKRD52, a promoter of miRNA-mediated silencing, as required for PD-1-independent T cell cytotoxicity by activating the JAK-STAT signaling and antigen presentation in cancer cells. ANKRD52 mutations found in prevalent cancer patients failed to activate the interferon-γ pathway and these patients exhibit poor overall survival. We hereby provide an approach for interrogating cancer genetic heterogeneity to uncover evolutionarily conserved evasion mechanism from host immunity. Citation Format: Tianyu Y. Song, Haixin Zhao, Hongjie Fan, Min Long, Chenlu Geng, Xiaoxiao Xie, Yang Liu, Wenrong Zhou, Ziyu Chen, Dawei Huang, Bo Peng, Zhengang Peng, Yong Cang. Immune pressure selects ANKRD52 mutations for cancer cells to escape T cell-mediated killing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2154.