Abstract 1905: In vivo CRISPR screen identifies tumor suppressors as drivers of tumor cell-intrinsic immune evasion

Cancer cell-intrinsic genetic alterations that allow cancer cells to evade destruction by the immune system remain poorly characterized. Here we performed a pooled CRISPR-Cas9-based in vivo genetic screen targeted to a pre-defined set of tumor suppressor genes to mimic loss-of-function mutations in syngeneic tumor models. CRISPR edited tumor cells were implanted into immune-deficient or immune-competent C57BL/6 mice, a subset of which were treated with anti-PD1 to simulate increased immune pressure. Tumor samples at the endpoint were subjected to next generation sequencing analysis to identify tumor suppressor genes driving immune evasion. The screen confirmed previously identified immunotherapy targets such as CD47 and Adar as well as known drivers of immune resistance in the interferon signaling and antigen presentation pathways. Importantly, we identified loss of STK11/LKB1 and KEAP1 as drivers of immune resistance in syngeneic models. TIL profiling analysis suggests that STK11/LKB1 knockout induces a “cold” tumor microenvironment. STK11/LKB1 and/or KEAP1 genomic alterations are found in ~25% of non-squamous non-small cell lung cancer and have been reported as a major predictor of primary resistance to PD-1 blockade. Together, these data demonstrate that high-throughput in vivo genetic screens can identify tumor cell-intrinsic drivers of immune evasion and establish murine system relevant to the study of primary resistance to PD-1 axis immunotherapy and more generally, tumor cell-intrinsic immune evasion. Citation Format: Chengyin Min, Ferdinandos Skoulidis, Wenrong Zhou, Jennifer Tsoi, Alan Huang, Matthew J. Goldstein. In vivo CRISPR screen identifies tumor suppressors as drivers of tumor cell-intrinsic 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 1905.