Title

Tumor-intrinsic PD-L1 promotes DNA repair in distinct cancers and suppresses PARP inhibitor-induced synthetic lethality

Authors

Anand V. Kornepati, UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANTONIO, San Antonio, Texas, United States.
Jacob T. Boyd, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Clare E. Murray, University of Texas Health San Antonio, San Antonio, TX, United States.
Julia Saifetyarova, University of Texas Health San Antonio, San Antonio, TX, United States.
Bárbara de la Peña Avalos, University of Texas Health San Antonio, San Antonio, TX, United States.
Cody M. Rogers, University of Texas Health San Antonio, San Antonio, TX, United States.
Haiyan Bai, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Alvaro S. Padron, University of Texas Health San Antonio, San Antonio, TX, United States.
Yiji Liao, The University of Texas Health Science Center at San Antonio, San Antonio, United States.
Carlos Ontiveros, UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANTONIO, San Antonio, Texas, United States.
Robert S. Svatek, UT Health San Antonio, San Antonio, Texas, United States.
Robert Hromas, The University of Texas Health Science Center at San Antonio, United States.
Rong Li, George Washington University, Washington, DC, United States.
Yanfen Hu, George Washington, Washington, DC, United States.
Jose R. Conejo-Garcia, Moffitt Cancer Center, Tampa, FL, United States.
Ratna K. Vadlamudi, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Weixing Zhao, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Eloise Dray, UT Health San Antonio, United States.
Patrick Sung, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Tyler J. Curiel, University of Texas Health San Antonio, San Antonio, TX, United States.

Document Type

Journal Article

Publication Date

3-3-2022

Journal

Cancer research

DOI

10.1158/0008-5472.CAN-21-2076

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 non-homologous 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 senstive to olaparib. By 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 co-factor BARD1 but instead co-immunoprecipitated with BARD1 and increased BRCA1 nuclear accumulation. Tumor PD-L1 depletion enhanced tumor CCL5 expression and TBK1 activation in vitro, similar to known immune-potentiating effects of PARP inhibitors. Collectively, these data define immune-dependent and -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.

Department

Biochemistry and Molecular Medicine

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