Immune checkpoint receptor (ICR) blockade as a cancer treatment strategy has yielded favorable response rates in some solid tumor types, yet cellular mechanisms of immune escape have resulted in limited efficacy in other tumors, including high grade serous carcinoma (HGSC). Our long-term goal is to understand the link between DNA damage repair (DDR) and HGSC immunogenicity, in order to develop combinatorial treatments for HGSC through DDR inhibition that turn hypoimmunogenic or ?cold? HGSC into ?hot? tumors with improved responses to immunotherapy. The current knowledge regarding DDR in HGSC has focused on the homologous recombination (HR) pathway. There is a fundamental gap in knowledge regarding the link between other DDR pathways and immune response; the objective of this proposal is to bridge that gap so that we can address the unmet need of treatment strategies for HGSC patients for whom immunotherapy or PARP inhibitor therapy, either alone or in combination, is ineffective. Our central hypothesis is that the inhibition of the non-homologous end joining (NHEJ) pathway is a novel immune priming strategy to sensitize cold HGSC to immune checkpoint blockade. Through the characterization of the role of NHEJ protein DEK in the pathogenesis of HGSC, we have identified a downstream targetable kinase, aurora kinase A (AURKA), that serves as a novel and potent checkpoint against DNA damage and type-I interferon (IFN-I) signaling. To test our central hypothesis, we will focus on three specific aims.
Aim 1. To test the hypothesis that the inhibition of NHEJ results in robust IFN-I signaling.
Aim 2. To characterize the mechanism by which the inhibition of NHEJ induces immune cell activation.
Aim 3. To test the hypothesis that NHEJ inhibition sensitizes cold HGSC to immune checkpoint blockade. The experiments for these aims will be carried out using human HGSC cell lines with known BRCA mutation status and HR-proficiency or HR-deficiency as well as primary, patient derived tumor cells established in cell culture. To characterize the immune changes following NHEJ inhibition in tumor cells and the interplay with host immune cells, we will employ the ID8/p53-/- and ID8/p53-/- /BRCA1-/- mouse cell lines on the C57BL/6 background to allow for studies utilizing established genetic knockouts of critical IFN-I signaling proteins. A second, genetically engineered mouse model of HGSC will also be studied. As outcomes of our work, we expect our findings to contribute to our understanding of the link between NHEJ and tumor immunogenicity. Furthermore, this work will provide critical insights into treatment strategies for HR proficient and BRCA wild-type cancers in which current PARP inhibitor-based therapies are less effective. These contributions will be significant, as they will define the underlying mechanisms and lead to effective combinatorial strategies for the treatment of HGSC and other solid malignancies, allowing us to move forward with immediate translation to clinical trials.
Immunotherapy is an exciting new frontier of anti-cancer therapy, yet response rates have been modest in many solid tumor types including high grade serous carcinoma (HGSC). We postulate that the inhibition of the non-homologous end joining pathway of DNA damage repair with agents including aurora kinase inhibitors triggers type I interferon signaling to sensitize cold HGSC to immune checkpoint receptor blockade. This combinatorial treatment approach has the potential for direct translation to clinical trials with the goal of improving patient outcomes.
