Abstract 1600: Cancer driver screens identifyregulators of immune checkpoint blockade therapy response

Abstract

Abstract Cancer mutations play essential roles in tumor development by promote cell proliferation or immune evasion. However, some recent researches indicate that cancer cells with these mutation burden also expose their vulnerability to immune-based therapies such as checkpoint blockade. Here we performed comprehensive CRISPR knockout library screens in syngeneic mouse models on cancer driver mutation genes. We identified a set of genes including Kmt2d, Arid2, Rhob, Eloc, Ptpn11 and Xpo1, which have high frequency mutation in several human cancer types and their deficiency made tumor cells better respond to anti-PD-1 treatment. Furthermore, some of these deletions were validated to sensitize the tumor cells to cytotoxic T cells by in vitro co-culture with CD8+ T cells. The findings of Kmt2d was in accordance with a recent report for its role as a sensitizing modulator of immune checkpoint blockade from mouse model and patient prediction. These findings provide a new insight for understanding the interaction between the tumor heterogeneity and microenvironment. These results revealed CRISPR in vivo screen as a robust tool for both context and target discovery for tumor immunotherapy. Citation Format: Wenrong Zhou, Zhengang Peng, Dawei Huang, Min Long, Tianyu Song, Siyuan Ni, Yong Cang. Cancer driver screens identifyregulators of immune checkpoint blockade therapy response [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 1600.