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

By Shiping Jiao, W. Xia, H. Yamaguchi, Yongkun Wei, Mei-Kuang Chen, Jung-Mao Hsu, J. Hsu, Wen-Hsuan Yu, Yi Du, Heng-Huan Lee and 8 more. Clinical Cancer Research, 2017

857 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/83d21c3e7e3ac5b76dc099f92a5fd821a57ac089

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Citations in the corpus

• Genetics and biology of prostate cancer (2018, background): “PARP inhibitors have yielded a high response rate in a subset of mCRPC patients with DNA repair defects (Mateo et al. 2015) and has been reported to induce PD-L1 expression in breast cancer (Jiao et al. 2017).”
• Mechanisms controlling PD-L1 expression in cancer (2019, background): “Remarkably, the inhibitor of PARP1, a negative regulator of EZH2 upregulates PD-L1 level (Jiao et al., 2017; Yamaguchi et al., 2018), implying that EZH2 may be another epigenetic regulator of PD-L1.”
• Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment (2019, background): “In addition, preclinical data have demonstrated upregulation of PD-L1 expression after exposure to PARP inhibition in triple-negative MDA-MB-231 cells, with subsequent resensitization to a PARP inhibitor when combined with a PD-L1 antibody (99).”
• Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “Combining PARPi and PD-L1 inhibitors can reactivate anti-tumor immunity [283].”
• Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022, background): “Moreover, PARPi upregulates PD-L1 expression by inactivating GSK3β signaling, which attenuates antitumor immunity [225].”
• Recent advances in therapeutic strategies for triple-negative breast cancer (2022, background): “These findings indicate that PARPi alone can reduce the anticancer effect through immune tolerance, but the combination of PARPi and PD-L1 blockade intensified the therapeutic efficacy [140].”