PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression

Shiping Jiao, Weiya Xia, Hirohito Yamaguchi, Yongkun Wei, Mei Kuang Chen, Jung Mao Hsu, Jennifer L. Hsu, Wen Hsuan Yu, Yi Du, Heng Huan Lee, Chia Wei Li, Chao Kai Chou, Seung Oe Lim, Shih Shin Chang, Jennifer Litton, Banu Arun, Gabriel N. Hortobagyi, Mien Chie Hung

Research output: Contribution to journalArticle

219 Scopus citations

Abstract

Purpose: To explore whether a cross-talk exists between PARP inhibition and PD-L1/PD-1 immune checkpoint axis, and determine whether blockade of PD-L1/PD-1 potentiates PARP inhibitor (PARPi) in tumor suppression. Experimental Design: Breast cancer cell lines, xenograft tumors, and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, IHC, and FACS analyses. The phospho-kinase antibody array screen was used to explore the underlying mechanism of PARPi-induced PD-L1 upregulation. The therapeutic efficacy of PARPi alone, PD-L1 blockade alone, or their combination was tested in a syngeneic tumor model. The tumor-infiltrating lymphocytes and tumor cells isolated from syngeneic tumors were analyzed by CyTOF and FACS to evaluate the activity of antitumor immunity in the tumor microenvironment. Results: PARPi upregulated PD-L1 expression in breast cancer cell lines and animal models. Mechanistically, PARPi inactivated GSK3β, which in turn enhanced PARPi-mediated PD-L1 upregulation. PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 resensitized PARPi-treated cancer cells to T-cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacy in vivo. Conclusions: Our study demonstrates a cross-talk between PARPi and tumor-associated immunosuppression and provides evidence to support the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach to treat breast cancer.

Original languageEnglish (US)
Pages (from-to)3711-3720
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
StatePublished - Jul 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression'. Together they form a unique fingerprint.

  • Cite this

    Jiao, S., Xia, W., Yamaguchi, H., Wei, Y., Chen, M. K., Hsu, J. M., Hsu, J. L., Yu, W. H., Du, Y., Lee, H. H., Li, C. W., Chou, C. K., Lim, S. O., Chang, S. S., Litton, J., Arun, B., Hortobagyi, G. N., & Hung, M. C. (2017). PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clinical Cancer Research, 23(14), 3711-3720. https://doi.org/10.1158/1078-0432.CCR-16-3215