期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 11, 页码 5951-5966出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI130445
关键词
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资金
- NCI Cancer Center Support grant [CA016672]
- Cancer Prevention and Research Institute of Texas [RP160242]
- Ovarian Cancer Research Foundation [5P50 CA217685-02, 7U01 CA217842-03, 5P50 CA098258-13, 545152]
- Adelson Medical Research Foundation [04-7023433]
- Developmental Research Program grant under MD Anderson Uterine Cancer Specialized Programs of Research Excellence (SPORE) in Uterine Cancer (NCI) [P50CA098258]
- NIH [CA181663]
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 ARID/A-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 AR1D1A 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 AR1D1A-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.
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