期刊
CANCER RESEARCH
卷 82, 期 11, 页码 2156-2170出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-2076
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资金
- NIH [F30-CA239390, TL1 TR002647]
- South Texas MSTP NIH [T32GM113896, R01-GM141091, R35 CA241801, R01CA205965, P30 CA054174]
- STARS, Owens Foundation
- UTHSA Daisy M. Skinner endowment
- Ovarian Cancer Research Alliance of Greater Cincinnati
- Clayton Foundation
- National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR002645]
BRCA1-mediated homologous recombination is regulated by the immune checkpoint molecule PD-L1, with genetic depletion of tumor PD-L1 affecting DNA repair mechanisms and sensitizing tumors to PARP inhibitors, highlighting a potential therapeutic vulnerability and response biomarker.
BRCA1-mediated homologous recombination is an important DNA repair mechanism that is the target of FDA-approved PARP inhibitors, yet details of BRCA1-mediated functions remain to be fully elucidated. Similarly, immune checkpoint molecules are tar-gets of FDA-approved cancer immunotherapies, but the biological and mechanistic consequences of their application are incompletely understood. We show here that the immune checkpoint molecule PD-L1 regulates homologous recombination in cancer cells by promoting BRCA1 nuclear foci formation and DNA end resection. Genetic depletion of tumor PD-L1 reduced homologous recombi-nation, increased nonhomologous end joining, and elicited syn-thetic lethality to PARP inhibitors olaparib and talazoparib in vitro in some, but not all, BRCA1 wild-type tumor cells. In vivo, genetic depletion of tumor PD-L1 rendered olaparib-resistant tumors sensitive to olaparib. In contrast, anti-PD-L1 immune checkpoint blockade neither enhanced olaparib synthetic lethality nor improved its efficacy in vitro or in wild-type mice. Tumor PD-L1 did not alter expression of BRCA1 or its cofactor BARD1 but instead coimmunoprecipitated with BARD1 and increased BRCA1 nuclear accumulation. Tumor PD-L1 depletion enhanced tumor CCL5 expression and TANK-binding kinase 1 activation in vitro, similar to known immune-potentiating effects of PARP inhibitors. Collec-tively, these data define immune-dependent and immune-independent effects of PARP inhibitor treatment and genetic tumor PD-L1 depletion. Moreover, they implicate a tumor cell-intrinsic, immune checkpoint-independent function of PD-L1 in cancer cell BRCA1-mediated DNA damage repair with translational potential, including as a treatment response biomarker. Significance: PD-L1 upregulates BRCA1-mediated homologous recombination, and PD-L1-deficient tumors exhibit BRCAness by manifesting synthetic lethality in response to PARP inhibitors, revealing an exploitable therapeutic vulnerability and a candidate treatment response biomarker. Significance: PD-L1 upregulates BRCA1-mediated homologous recombination, and PD-L1-deficient tumors exhibit BRCAness by manifesting synthetic lethality in response to PARP inhibitors, revealing an exploitable therapeutic vulnerability and a candidate treatment response biomarker. [GRAPHICS] .
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