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, 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
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 vivoConclusions: 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.
Conflict of interest statement
Conflicts of Interest
The authors have declared that no conflict of interest exists.
©2017 American Association for Cancer Research.
Figures
![Figure 1. PARPi upregulates PD-L1 protein expression…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5511572/bin/nihms850682f1.jpg)
![Figure 2. PARPi upregulates PD-L1 expression in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5511572/bin/nihms850682f2.jpg)
![Figure 3. GSK3β inactivation is required for…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5511572/bin/nihms850682f3.jpg)
![Figure 4. Olaparib attenuates PD-1 binding and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5511572/bin/nihms850682f4.jpg)
Figure 5. PARPi-induced PD-L1 upregulation suppresses anticancer…
Figure 5. PARPi-induced PD-L1 upregulation suppresses anticancer immunity and blockade of PD-L1 potentiates PARPi
(A)…
Figure 6. Inverse correlation between PAR and…
Figure 6. Inverse correlation between PAR and PD-L1 in surgical specimens of breast cancer
Top,…
![Figure 5. PARPi-induced PD-L1 upregulation suppresses anticancer…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5511572/bin/nihms850682f5.jpg)
![Figure 6. Inverse correlation between PAR and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5511572/bin/nihms850682f6.jpg)
Source: PubMed