A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block “eat-me” signal  

作　　者：Min Luo Xueping Wang Shaocong Wu Chuan Yang Qiao Su Lamei Huang Kai Fu Sainan An Fachao Xie Kenneth Kin Wah To Fang Wang Liwu Fu 

机构地区：[1]State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine,Guangdong Esophageal Cancer Institute,Sun Yat-sen University Cancer Center,Guangzhou 510060,P.R.China [2]Laboratory Animal Centre,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou 510080,P.R.China [3]School of Pharmacy,The Chinese University of Hong Kong,Hong Kong,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第9期4403-4415,共13页信号转导与靶向治疗（英文）

基　　金：National Natural Science Foundation of China(U21A20421);National Natural Science Foundation of China(82073882);National Natural Science Foundation of China(82203649);Guangdong Basic and Applied Basic Research Foundation(2020B1515120032);China Postdoctoral Science Foundation(2021M693648);Guangdong Esophageal Cancer Institute Science and Technology Program(M202001).

摘　　要：Immune checkpoint inhibitors(ICIs)have induced durable clinical responses in a subset of patients with colorectal cancer(CRC).However,the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies.Inflammation-related molecule A20 is closely related to cancer immune response,but the effect of A20 on“eat-me”signal and immunotherapy efficacy remains elusive.We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo.Higher A20 expression was associated with less infiltration of immune cells including CD3(+),CD8(+)T cells and macrophages in CRC tissues and also poorer prognosis.Gain-and loss-A20 functional studies proved that A20 could decrease the“eat-me”signal calreticulin(CRT)protein on cell membrane translocation via upregulating stanniocalcin 1(STC1),binding to CRT and detaining in mitochondria.Mechanistically,A20 inhibited GSK3βphosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein.Our findings reveal a new crosstalk between inflammatory molecule A20 and“eat-me”signal in CRC,which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.

关 键 词：STC1 GSK3Β A20 

分 类 号：R735.34[医药卫生—肿瘤]