癌症研究
免疫疗法
胰腺癌
癌症免疫疗法
癌症
蛋白激酶A
生物
医学
计算生物学
激酶
内科学
细胞生物学
作者
Wenhua Sang,Yiduo Zhou,Haiyan Chen,Chengxuan Yu,Lisi Dai,Zhaobo Liu,Lang Chen,Yimin Fang,Pingping Ma,Xiaochong Wu,Hao Kong,Wenting Liao,Jingping Hong,Junbin Qian,Da Wang,Yun-Hua Liu
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2023-10-12
卷期号:14 (2): 326-347
被引量:3
标识
DOI:10.1158/2159-8290.cd-23-0584
摘要
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancies due to its aggressive nature and the paucity of effective treatment options. Almost all registered drugs have proven ineffective in addressing the needs of PDAC patients. 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 RIPK2 is a crucial driver of immune evasion of cytotoxic T-cell killing and that genetic or pharmacological targeting of RIPK2 sensitizes PDAC to 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-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.
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