Mechanisms of selective therapeutic synergy of PARP-inhibition and CTLA4 blockade engaged by interferon-gamma in the ovarian tumor microenvironment

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The high mortality rate associated with ovarian cancer results from the failure of tumor-directed therapy to produce lasting treatment responses. Durable survival in patients with other solid tumors has recently been achieved using immune checkpoint antibodies, however similar results have not been observed in women with ovarian cancer. Published work from our lab demonstrates that combining poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors with immune checkpoint blockade can achieve long- term survival in ovarian cancer models. Early results from an ongoing clinical trial have now demonstrated significant clinical efficacy of this regimen in women with recurrent ovarian cancer. Here we propose to dissect the mechanisms responsible for the observed therapeutic synergy of this combination to enable the optimal integration of immune therapy with cytotoxic regimens for long-term benefit in women with ovarian cancer. The scientific premise for this study is based accumulating evidence of a dynamic interaction between tumor cells and the tumor microenvironment (TME) that regulates treatment response and disease outcomes. Our work additionally demonstrates that the TME interacts directly with tumor- targeted agents to enhance tumor clearance. Combined PARP-inhibition and CTLA4 blockade resulted in a significant increase in the proportion of T cells producing IFNγ in the TME, an effect which persisted long after completion of therapy. We found that IFNγ enhanced tumor cytotoxicity in response to PARP- inhibition through a cell-intrinsic mechanism in vitro, and that IFNγ was required for the survival benefit observed in vivo. Evidence that conditions in the tumor environment significantly modulate the therapeutic efficacy of PARP-inhibitors, termed “contextual synthetic lethality”, presents an opportunity to maximize patient outcomes and target treatment effects to the TME. Here we propose to dissect the cell-intrinsic and –extrinsic mechanisms responsible for the observed therapeutic synergy of PARP inhibitors and CTLA4 blockade and to develop a treatment predictive biomarker linked to these mechanisms for clinical translation. With the rapid adoption of immune checkpoint antibodies and PARP-inhibitors for the treatment of ovarian cancer and other tumor types, this proposal has potential for immediate clinical impact through current and planned clinical trials.