Tumor cell instrinsic DNA damage signaling to the immune response

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Summary The efficacy of DNA damaging cancer therapies is determined by the (i) intrinsic DNA repair capacity of cancer cells, and (ii) immune responses to signals emanating from tumors. Understanding the molecular basis of communication between the DNA damage and immune responses is therefore a central issue to both cancer etiology and therapy. We reported that mitotic progression after DNA damage allows cGAS-STING dependent pattern recognition of DNA in micronuclei to initiate interferon-stimulated gene expression and T-cell dependent eradication of distant metastases. Disruption of DNA damage induced cell cycle checkpoints together with p53 mutation resulted in pattern recognition receptor responses by both DNA and RNA sensors, including the cGAS-STING and the MDA5 and RIG-I/MAVs pathways. Our unpublished findings reveal additional complexity to these responses. NLRP9 inflammasome assembly is increased in chromosomally instable cancer cells and opposes interferon stimulated responses. Interestingly, NLRP9 deficiency delayed tumor formation in a murine Brca2 mutant high grade serous ovarian cancer model commensurate with reversal of an immune suppressive tumor microenvironment. These findings potentially explain how DNA damage can either activate or suppress anti-tumor immune responses. This proposal will take cellular, biochemical, and in vivo approaches to test hypotheses that chromosome instability activates dichotomous inflammatory signaling responses that differentially affect tumor growth. The importance of these mechanisms to cancer immunotherapy will be tested in syngeneic tumor models that assess systemic anti-tumor immune responses to combinations of DNA damaging therapies and immune checkpoint blockade. Collaborations with Projects 2 and 3, and with the Mammalian Artificial Chromosome and Chemical Biology Cores will be instrumental to these studies.