Abstract 1356: In vivo epigenetic CRISPR screen identifies PRMT5 as an immune suppressor in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is a devastating disease in which the mortality rate approaches the incidence rate. Desmoplasia is a hallmark of PDA, which creates a mechanical barrier surrounding the tumor cells, prevents appropriate vascularization and leads to pool immune infiltration. PDA exhibits a “cold” tumor microenvironment characterized by a prominent myeloid cell infiltration, which is extremely immune suppressive. Therefore, PDA has been demonstrated to be resistant to immunotherapy. Indeed, single-agent immune checkpoint inhibitor therapy has failed in clinical trials for PDA patients. Targeting epigenetic modification is an attractive approach to enable the response to immunotherapy in multiple solid tumor models. To identify epigenetic modulators as potential novel immunotherapeutic targets in PDA, we performed an orthotopic in vivo epigenetic CRISPR screen. Prmt5 was screened out as one of the top candidates. Further validation studies showed that Prmt5 knockdown (KD) alone or in combination with anti PD-1 treatment significantly inhibited the tumor progression. PRMT5 shRNA in combination with PD1 blockade can dramatically altered the tumor immune microenvironment (TME) with influx of effector CD8 T cells and changes in the macrophage/myeloid populations. Collectively, our work describes PRMT5 as an attracting target which governs tumor immunity in PDA. Citation Format: Hai Hu, Jiehui Deng, Fei Li, wei wang, Alireza Khodadadi-Jamayran. In vivo epigenetic CRISPR screen identifies PRMT5 as an immune suppressor in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1356.