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

Publication ,  Journal Article
Kornepati, AVR; Boyd, JT; Murray, CE; Saifetiarova, J; de la Peña Avalos, B; Rogers, CM; Bai, H; Padron, AS; Liao, Y; Ontiveros, C; Svatek, RS ...
Published in: Cancer Res
June 6, 2022

UNLABELLED: 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 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. See related commentary by Hanks, p. 2069.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

June 6, 2022

Volume

82

Issue

11

Start / End Page

2156 / 2170

Location

United States

Related Subject Headings

  • Synthetic Lethal Mutations
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Phthalazines
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice
  • Humans
  • DNA Repair
  • Cell Line, Tumor
  • BRCA1 Protein
 

Citation

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Kornepati, A. V. R., Boyd, J. T., Murray, C. E., Saifetiarova, J., de la Peña Avalos, B., Rogers, C. M., … Curiel, T. J. (2022). Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor-Induced Synthetic Lethality. Cancer Res, 82(11), 2156–2170. https://doi.org/10.1158/0008-5472.CAN-21-2076
Kornepati, Anand V. R., Jacob T. Boyd, Clare E. Murray, Julia Saifetiarova, Bárbara de la Peña Avalos, Cody M. Rogers, Haiyan Bai, et al. “Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor-Induced Synthetic Lethality.Cancer Res 82, no. 11 (June 6, 2022): 2156–70. https://doi.org/10.1158/0008-5472.CAN-21-2076.
Kornepati AVR, Boyd JT, Murray CE, Saifetiarova J, de la Peña Avalos B, Rogers CM, et al. Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor-Induced Synthetic Lethality. Cancer Res. 2022 Jun 6;82(11):2156–70.
Kornepati, Anand V. R., et al. “Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor-Induced Synthetic Lethality.Cancer Res, vol. 82, no. 11, June 2022, pp. 2156–70. Pubmed, doi:10.1158/0008-5472.CAN-21-2076.
Kornepati AVR, Boyd JT, Murray CE, Saifetiarova J, de la Peña Avalos B, Rogers CM, Bai H, Padron AS, Liao Y, Ontiveros C, Svatek RS, Hromas R, Li R, Hu Y, Conejo-Garcia JR, Vadlamudi RK, Zhao W, Dray E, Sung P, Curiel TJ. Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor-Induced Synthetic Lethality. Cancer Res. 2022 Jun 6;82(11):2156–2170.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

June 6, 2022

Volume

82

Issue

11

Start / End Page

2156 / 2170

Location

United States

Related Subject Headings

  • Synthetic Lethal Mutations
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Phthalazines
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice
  • Humans
  • DNA Repair
  • Cell Line, Tumor
  • BRCA1 Protein