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

Abstract

Purpose To explore whether a crosstalk exists between PARP inhibition and PD-L1/ PD-1 immune checkpoint axis, and determine if 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, immunohistochemistry 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 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 anti-tumor immunity in the tumor microenvironment. Results PARPis 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 re-sensitized 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. Conclusion Our study demonstrates a crosstalk 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.

DNA Damage and Repair Biomarkers of Immunotherapy Response

“…Administration of BMN 673, a PARP1 inhibitor, increased intratumoral CD8 + T cells and drove production of IFNγ and TNFα in syngeneic BRCA1 -deficient murine ovarian tumors[181], and adding CTLA-4 blockade to PARP inhibition further increased IFNγ production and T cell activation and extended survival compared to PARP inhibition alone. [182] However, PARP inhibition may also induce immunosuppressive effects such as upregulation of PD-L1[183], providing further rationale for combining ICB with PARP inhibition.…”

Complex interplay between tumor microenvironment and cancer therapy

“…For example, using the cis-Apc/Smad4 mouse model of locally invasive intestinal adenocarcinoma, Fujishita et al found that mTOR inhibitors administration induced the activation of EGFR and MEK/ERK signaling in stromal cells, leading to treatment resistance [103]. In contrast to BRCA-deficient ovarian cancer model, olaparib and talazoparib, which are PARP inhibitors, upregulated PD-L1 expression via GSK3β signaling and induced an immune suppressive TME in breast cancer models [104]. In addition, therapeutic mAb cetuximab that targeted EGFR increased the tumor-promoting TAMs in TME and attenuated treatment responses [105].…”

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

“…Several recent pre-clinical studies suggest that PARP inhibition enhances immunogenicity in models of ovarian and breast cancer and that combining the two results in synergistic effects [73][74][75]. TOPACIO, a multicenter, open-label phase 1/2 study evaluated the PARP inhibitor niraparib plus pembrolizumab in metastatic TNBC and advanced ovarian cancer and during the dose-finding portion of the trial, none of the eight evaluable patients progressed: 4/8 had objective response and 4/8 had stable disease [71].…”