单位：[1]Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA[2]Department of Medical Oncology, Tongji Hospital, The University of Huazhong Science & Technology, Wuhan, China华中科技大学同济医学院附属同济医院肿瘤科[3]Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA[4]Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA[5]Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA[6]Department of Cell Development and Cancer Biology, Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon, USA[7]Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
ARID1A, a component of the chromatin-remodeling complex SWI/SNF, is one of the most frequently mutated genes in human cancer. We sought to develop rational combination therapy to potentiate the efficacy of immune checkpoint blockade in ARID1A-deficient tumors. In a proteomic analysis of a data set from The Cancer Genomic Atlas, we found enhanced expression of Chk2, a DNA damage checkpoint kinase, in ARID1A-mutated/deficient tumors. Surprisingly, we found that ARID1A targets the nonchromatin substrate Chk2 for ubiquitination. Loss of ARID1A increased the Chk2 level through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation. Inhibition of the ATM/Chk2 DNA damage checkpoint axis led to replication stress and accumulation of cytosolic DNA, which subsequently activated the DNA sensor STING-mediated innate immune response in ARID1A-deficient tumors. As expected, tumors with mutation or low expression of both ARID1A and ATM/Chk2 exhibited increased tumor-infiltrating lymphocytes and were associated with longer patient survival. Notably, an ATM inhibitor selectively potentiated the efficacy of immune checkpoint blockade in ARID1A-depleted tumors but not in WT tumors. Together, these results suggest that ARID1A's targeting of the nonchromatin substrate Chk2 for ubiquitination makes it possible to selectively modulate cancer cell-intrinsic innate immunity to enhance the antitumor activity of immune checkpoint blockade.
基金：
This research was supported by NCI Cancer Center Support grant
CA016672 to The University of Texas MD Anderson Cancer
Center; NIH R01 grant CA181663 to GP; Cancer Prevention and
Research Institute of Texas grant RP160242 to XS and GP; Ovarian Cancer Research Foundation grants 5P50 CA217685-02, 7U01
CA217842-03, 5P50 CA098258-13, and 545152; Adelson Medical
Research Foundation grant 04-7023433 to GBM; and a Developmental Research Program grant to GP under the MD Anderson
Uterine Cancer Specialized Programs of Research Excellence
(SPORE) in Uterine Cancer (NCI grant P50CA098258).
第一作者单位：[1]Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
共同第一作者：
通讯作者：
通讯机构：[*1]1515 Holcombe Boulevard, Houston, Texas 77030, USA.
推荐引用方式(GB/T 7714)：
Wang Lulu,Yang Lin,Wang Chen,et al.Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors.[J].JOURNAL OF CLINICAL INVESTIGATION.2020,130(11):5951-5966.doi:10.1172/JCI130445.
APA：
Wang Lulu,Yang Lin,Wang Chen,Zhao Wei,Ju Zhenlin...&Peng Guang.(2020).Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors..JOURNAL OF CLINICAL INVESTIGATION,130,(11)
MLA：
Wang Lulu,et al."Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors.".JOURNAL OF CLINICAL INVESTIGATION 130..11(2020):5951-5966
医学