Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer  

作　　者：Chaofan Liu Xi Wang Wan Qin Jingyao Tu Chunya Li Weiheng Zhao Li Ma Bo Liu Hong Qiu Xianglin Yuan 

机构地区：[1]Department of Oncology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,P.R.China

出　　处：《Cancer Communications》2023年第4期435-454,共20页癌症通讯（英文）

基　　金：Innovative Capacity Building Project of the Hubei Engineering Research Center for Radiotherapy and Radiation Protection of Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Grant/Award Number:2018-420114-35-03-071705;State Key Program of National Natural Science of China,Grant/Award Number:82130092;National Natural Science Foundation of China,Grant/Award Numbers:81372664,81902619。

摘　　要：Background:Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and programmed death-ligand 1(PD-L1)have shown a moderate response in colorectal cancer(CRC)with deficient mismatch repair(dMMR)functions and poor response in patients with proficientMMR(pMMR).pMMRtumors are generally immunogenically“cold”,emphasizing combination strategies to turn the“cold”tumor“hot”to enhance the efficacy of ICIs.ATR inhibitors(ATRi)have been proven to cooperate with radiation to promote antitumor immunity,but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs.This study aimed to investigate the efficacy of combining ATRi,irradiation(IR),and anti-PD-L1 antibodies in CRC mouse models with different microsatellite statuses.Methods:The efficacy of combining ATRi,IR,and anti-PD-L1 antibodies was evaluated in CRC tumors.The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens.The mechanisms were explored via cell viability assay,flow cytometry,immunofluorescence,immunoblotting,co-immunoprecipitation,and real-time quantitative PCR in multiple murine and human CRC cell lines.Results:Combining ATRi berzosertib and IR enhanced CD8+T cell infiltration and enhanced the efficacy of anti-PD-L1 therapy in mouse CRC models with different microsatellite statuses.The mechanistic study demonstrated that IR+ATRi could activate both the canonical cGAS-STING-pTBK1/pIRF3 axis by increasing cytosolic double-stranded DNA levels and the non-canonical STING signaling by attenuating SHP1-mediated inhibition of the TRAF6-STINGp65 axis,via promoting SUMOylation of SHP1 at lysine 127.By boosting the STING signaling,IR+ATRi induced type I interferon-related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment,thus facilitating immunotherapy.Conclusions:The combination of ATRi and IR could facilitate anti-PD-L1 therapy by promoting STING signaling in CRC models with different microsat

关 键 词：colorectal cancer ATR inhibitor radiotherapy immune checkpoint inhibitor PD-L1 innate immunity cGAS-STING DNA damage SHP1 SUMOYLATION 

分 类 号：R730.51[医药卫生—肿瘤]