PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression

• Published in: Clinical cancer research Vol. 23; no. 14; pp. 3711 - 3720
• Main Authors: Jiao, Shiping, Xia, Weiya, Yamaguchi, Hirohito, Wei, Yongkun, Chen, Mei-Kuang, Hsu, Jung-Mao, Hsu, Jennifer L., Yu, Wen-Hsuan, Du, Yi, Lee, Heng-Huan, Li, Chia-Wei, Chou, Chao-Kai, Lim, Seung-Oe, Chang, Shih-Shin, Litton, Jennifer, Arun, Banu, Hortobagyi, Gabriel N., Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.07.2017
• Subjects: Animal models; Animals; Anticancer properties; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Biotechnology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Cancer; Cell culture; Cell Line, Tumor; Experimental design; Female; Flow cytometry; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immune checkpoint; Immunity; Immunoblotting; Immunosuppression; In vivo methods and tests; Inhibitors; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Mice; PD-1 protein; PD-L1 protein; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - immunology; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage; Poly(ADP-ribose) Polymerase Inhibitors - immunology; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Tumor cell lines; Tumor cells; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumor suppression; Tumor-infiltrating lymphocytes; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-3215

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. Clin Cancer Res; 23(14); 3711–20. ©2017 AACR.