机构：[1]Department of Colorectal Surgery & Oncology of the Second Affiliated Hospital, and Department of Pathology & Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China[2]Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China浙江大学医学院附属妇产科医院[3]Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China[4]Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China[5]Department of Pancreatic Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China四川大学华西医院[6]Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China[7]Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, China[8]Zhejiang University Cancer Center, Hangzhou, China[9]Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China
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.
基金：
This work was supported by National Natural Science Foundation
of China (82072615 and 82273274, to Y. Liu; 82173150, to J. Qian;
82303951, to D. Wang; and 82073158, to H. Jiang) and Leading
Innovative, Entrepreneur Team Introduction Program of Zhejiang
(2019R01007, to Y. Liu) and Zhejiang Province Natural Science Fund
for Excellent Young Scholars (LR22H160004, to J. Qian).
第一作者机构：[1]Department of Colorectal Surgery & Oncology of the Second Affiliated Hospital, and Department of Pathology & Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Colorectal Surgery & Oncology of the Second Affiliated Hospital, and Department of Pathology & Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China[2]Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China[4]Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China[5]Department of Pancreatic Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China[7]Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, China[8]Zhejiang University Cancer Center, Hangzhou, China[9]Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, China[*1]West China Hospital, Sichuan University, Chengdu, China.[*2]Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China[*3]Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China[*4]Department of Pathology & Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China.
推荐引用方式(GB/T 7714)：
Wenhua Sang,Yiduo Zhou,Haiyan Chen,et al.Receptor-interacting protein kinase 2 is an immunotherapy target in pancreatic cancer[J].CANCER DISCOVERY.2024,14(2):326-347.doi:10.1158/2159-8290.CD-23-0584.
APA：
Wenhua Sang,Yiduo Zhou,Haiyan Chen,Chengxuan Yu,Lisi Dai...&Yun-Hua Liu.(2024).Receptor-interacting protein kinase 2 is an immunotherapy target in pancreatic cancer.CANCER DISCOVERY,14,(2)
MLA：
Wenhua Sang,et al."Receptor-interacting protein kinase 2 is an immunotherapy target in pancreatic cancer".CANCER DISCOVERY 14..2(2024):326-347
医学