posted on 2024-02-08, 08:21authored byWenhua Sang, Yiduo Zhou, Haiyan Chen, Chengxuan Yu, Lisi Dai, Zhongkun Liu, Lang Chen, Yimin Fang, Panpan Ma, Xiangji Wu, Hao Kong, Wenting Liao, Hong Jiang, Junbin Qian, Da Wang, Yun-Hua Liu
Supplementary Table S1. MAGeCK analysis of CRISPR screen results to identify regulator of immune evasion in orthotopic PDAC mouse models.
Funding
National Natural Science Foundation of China (NSFC)
History
ARTICLE ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy because of its aggressive nature and the paucity of effective treatment options. Almost all registered drugs have proven ineffective in addressing the needs of patients with PDAC. This is the result of a poor understanding of the unique tumor–immune microenvironment (TME) in PDAC. To identify druggable regulators of immunosuppressive TME, we performed a kinome- and membranome-focused CRISPR screening using orthotopic PDAC models. Our data showed that receptor-interacting protein kinase 2 (RIPK2) is a crucial driver of immune evasion of cytotoxic T-cell killing and that genetic or pharmacologic targeting of RIPK2 sensitizes PDAC to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy, leading to prolonged survival or complete regression. Mechanistic studies revealed that tumor-intrinsic RIPK2 ablation disrupts desmoplastic TME and restores MHC class I (MHC-I) surface levels through eliminating NBR1-mediated autophagy-lysosomal degradation. Our results provide a rationale for a novel combination therapy consisting of RIPK2 inhibition and anti–PD-1 immunotherapy for PDAC.
PDAC is resistant to almost all available therapies, including immune checkpoint blockade. Through in vivo CRISPR screen, we identified that RIPK2 plays a crucial role in facilitating immune evasion by impeding antigen presentation and cytotoxic T-cell killing. Targeting tumor-intrinsic RIPK2 either genetically or pharmacologically improves PDAC to anti–PD-1 immunotherapy.See related commentary by Liu et al., p. 208.This article is featured in Selected Articles from This Issue, p. 201