Abstract
BackgroundImmune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. However, the effects of Niraparib, one of the poly (ADP) ribose polymerase (PARP) inhibitors, on the immune response remains unclear. Delineating the crosstalk between cytotoxic anticancer agents and cancer-associated immunity may lead to more efficient combinatorial strategies.MethodsProgrammed death ligand 1 (PD-L1) expression in human ovarian cancer cells after PARP inhibitors treatment was examined by western blotting (WB) and flow cytometry. The expression of poly ADP-ribose polymerase (PARP1), PD-L1, and CD8 in human ovarian cancer tissues was detected by immunohistochemistry(IHC). The effect of Niraparib and PD-L1 blockade in ovarian cancer progression was investigated in vivo. The changes of immune cells and cytokines in vitro and in vivo were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Changes of cGAS/STING signal pathway after Niraparib treatment were determined by WB, ELISA.ResultsNiraparib upregulated membrane PD-L1 and total PD-L1 expression in ovarian cancer cells and had a synergistic effect with PD-L1 blockade in vivo. In clinical patient samples, Niraparib augmented cytotoxic CD8+T cell proportion and function. In vivo and vitro, Niraparib can also increase the proportion of T cells and combined with PD-L1 blockade could further enhance the effect. Besides, Niraparib activated the cGAS-STING pathway, increasing the levels of cytokines such as CCL5 and CXCL10, which played a vital role in augmenting the infiltration and activation of cytotoxic T cells.ConclusionsNiraparib could modulate the immune response via the activation of the cGAS/STING pathway, and combination with PD-L1 blockade could further enhance the effect. These results provide a sound theoretical basis for clinical treatment.
Highlights
Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management
SKOV3 and UWB1.289 cells were transfected with siRNAs using Lipofectamine 2000 (Invitrogen, CA) according to the manufacture’s instructions, PARP1 and Programmed death ligand 1 (PD-L1) protein levels were determined by western blotting and flow cytometry
poly (ADP) ribose polymerase (PARP) inhibitors upregulated the expression of PD-L1 protein in both cell lines, and Niraparib increased the expression of PD-L1 steadily (Fig. 1B, Additional file 1: Figure S1B)
Summary
Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. Drugs targeting the DNA damage response (DDR) pathway such as Olaparib and Niraparib have been utilized for ovarian cancer therapy. Niraparib was recently approved by the United States Food and Drug Administration (FDA) for treating patients with recurrent, platinum-sensitive ovarian cancer after at least two previous chemotherapy treatments [7]. Despite the profound and sustained anti-tumor responses observed in treating ovarian cancer patients, resistance to PARP inhibitors has emerged in some cases [8]. To overcome this resistance, it is necessary to explore combinations with other agents, such as immunotherapies
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