Background: We recently demonstrated that treatment with poly(ADP-ribose) polymerase (PARP) inhibitors sensitize BRCA1-deficient ovarian cancers to immune checkpoint blockade in preclinical models. The extended survival in response to this combination was associated with a significant increase in IFNg producing effector T cells in the tumor environment. In vitro experiments identified a significant interaction between PARP-inhibition and IFNg that promoted tumor cytotoxicity in a caspase-independent manner. We hypothesized that IFNg engages immunogenic cell death mechanisms in response to PARP-inhibition to promote immune-mediated tumor clearance.

Methods: To distinguish cell death mechanisms in vitro, we exposed ovarian cancer cells to a PARP-inhibitor (10 microg/ml) and IFNg (2 ng/ml). Calreticulin translocation to the cell membrane and the release of high-mobility group protein 1 (HMGB-1) were assessed as characteristic features of immunogenic cell death. Innate cell activation was evaluated by analysis of dendritic cells in draining lymph nodes after vaccination. Evidence of immunogenicity was confirmed in vivo with vaccination studies.

Results: Tumor cells treated with a PARP-inhibitor in combination with IFNg, but not the cells exposed to the PARP-inhibitor alone, demonstrated calreticulin translocation and HMGB-1 release. In vivo, vaccination using cells treated with both the PARP-inhibitor and IFNg protected animals from intraperitoneal tumor challenge. Vaccinated mice also rejected secondary and tertiary tumor challenges demonstrating durable protective memory. Vaccinated tumor cells were phagocytosed by DCs in draining lymph nodes and induced co-stimulatory ligand and MHC expression. Adoptive transfer of splenocytes from vaccinated animals confirmed that this protective effect was T cell-mediated.

Conclusions: These results identify a novel mechanism by which PARP-inhibition drives immunogenic cell death in response to IFNg in the ovarian tumor environment. These effects can be leveraged to enhance tumor clearance in combination with immune therapy, and may present a strategy to circumvent adaptive treatment resistance associated with high levels of IFNg in the tumor microenvironment.

Citation Format: Ichiko Kinjyo, Sarah F. Adams. PARP-inhibition induces cancer immunogenic cell death in response to high levels of interferon-gamma in the tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 958.