Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor-Induced Synthetic Lethality

Anand V.R. Kornepati, Jacob T. Boyd, Clare E. Murray, Julia Saifetiarova, Bárbara de la Peña Avalos, Cody M. Rogers, Haiyan Bai, Alvaro S. Padron, Yiji Liao, Carlos Ontiveros, Robert S. Svatek, Robert Hromas, Rong Li, Yanfen Hu, Jose R. Conejo-Garcia, Ratna K. Vadlamudi, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J. Curiel

Research output: Contribution to journalArticlepeer-review

Abstract

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 targets 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 recombination, increased nonhomologous end joining, and elicited synthetic 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. Collectively, these data define immune-dependent and immuneindependent 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.

Original languageEnglish (US)
Pages (from-to)2156-2170
Number of pages15
JournalCancer Research
Volume82
Issue number11
DOIs
StatePublished - Jun 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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