Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors have been a remarkable breakthrough in the treatment of ovarian cancers with BRCA1/2 mutations. We have previously reported that PARP-inhibition with immune checkpoint blockade extended survival of BRCA1-deficient ovarian cancer (ov ca) preclinical models. A significant increase in IFNg producing effector T cells in the tumor environment promoted tumor cytotoxicity in a caspase-independent manner. In this study, we hypothesized that in the presence of IFNg, PARPi may induce immunogenic cell death (ICD) rather than apoptosis and promote immune-mediated tumor control. In vitro, PARPi+IFNg treatment induces hallmarks of ICD in BRCAmt ov ca; such as cell surface translocation of calreticulin, ATP and HMGB-1 release but not by PARPi or IFNg single treatment. Additionally, the PARPi+IFNg treated Ov ca cells induced maturation and activation of dendritic cells with enhanced antigen-presentation to stimulate anti-tumor T cells. Evidence of immunogenicity was confirmed by the benefit of vaccination with PARPi+IFNg treated Ov ca cells in vivo. The vaccination established the long-lasting protective anti-tumor immune responses to clear sequential tumor inoculations. T cell-depletion and adoptive transfer experiments showed the ICD-induced tumor immunity was surprisingly, both CD4 and CD8 T cell-mediated. Currently, we are addressing whether anti-tumor antibodies contribute to tumor control. Our results identified a novel mechanism by which PARP-inhibition with IFNg induces ICD in the ovarian tumor environment. These effects can be leveraged to enhance tumor clearance in the combination with immune therapies to modulate TME by stimulating tumor-immune cycles. Supported by grants from NCI (R37 CA229221)
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