Journal
CLINICAL CANCER RESEARCH
Volume 23, Issue 14, Pages 3711-3720Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-3215
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Funding
- NIH [CCSG CA016672]
- Cancer Prevention & Research Institutes of Texas [DP150052, RP160710]
- Breast Cancer Research Foundation
- Patel Memorial Breast Cancer Endowment Fund
- National Breast Cancer Foundation, Inc.
- University of Texas MD Anderson Cancer Center-China Medical University and Hospital Sister Institution Fund
- Ministry of Science and Technology
- International Research-intensive Centers of Excellence in Taiwan (I-RiCE) [MOST 105-2911-I-002-302]
- Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence [MOHW106-TDU-B-212-144003]
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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 GSK3b, 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. (C) 2017 AACR.
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