Abstract 3140: Tumor evolution selectively inactivates microRNA machinery for immune evasion

Abstract Cancer arises after somatic mutations override cellular and immunological control of cell proliferation1. Mutations in oncogenes and tumor suppressor genes endow cancer cells intrinsic growth advantage over neighboring cells. Mutations can also enable cancer cells to escape from immune surveillance during cancer evolution, but a targeted approach to uncover such mutations is lacking. We hypothesized that genetic heterogeneity intrinsic to cancer cells affects the cell fitness to T cell-mediated cytotoxicity. By deep sequencing of murine tumors grown under different conditions of immune editing, we identified 59 genetic mutations in clonal populations that were specifically enriched under host immune pressure. To differentiate driver from passenger mutations against immune selection, we performed in vivo and T cell co-culture CRISPR screens with a guide RNA library targeting the corresponding genes. We identified ANKRD52 as required for PD-1-independent T cell-mediated cytotoxicity, which enhanced the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells. ANKRD52, in complex with PPP6C, dephosphorylates AGO26 and promoted microRNA (miRNA)-targeted silencing of suppressor of cytokine signaling 1 (SOCS1), and deletion of SOCS1 reinstalled the sensitivity of the mutant cells to T cell killing. Introduction of patient hotspot ANKRD52 mutations, or deletion of AGO2, DICER1 or XPO5 in cancer cells compromised the interferon-γ and T cell response. Remarkably, expression of the core miRNA biogenesis and targeting machinery strongly correlates with intratumoral T cell abundance across nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway is exploited by cancer cells for immune escape. Citation Format: Haixin Zhao, Tian-yu Song, Min Long, Hong-Jie Fan, Yang Liu, Chen-Lu Geng, Xiaoxiao Xie, Dawei Huang, Zhengang Peng, Bo Peng, Yong Cang. Tumor evolution selectively inactivates microRNA machinery for immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3140.