Genome Instability Induced Anti-Tumor Immune Responses

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Summary The overarching objective of this Program Project Grant is to understand fundamental mechanisms underlying communication between cancer cell genomic instability and the immune system. Foundational work from the investigators on this P01 demonstrates multivariate ways in which genomic damage is aberrantly detected as “foreign” by pattern recognition receptors that are typically used to sense viral nucleic acids. The collective body of work from our groups establish that DNA damage, changes in tissue architecture, mitotic errors, and nuclear envelope fragility serve to breach cell intrinsic barriers that prevent endogenous DNA and RNA from detection by innate immune pattern recognition sensors. These events critically affect the tumor microenvironment to either promote or suppress tumor growth. To achieve our goals, we have assembled three Projects that will work closely with three Cores to address critical questions on detection of genome instability in tumors by the immune response. Project 1 investigates the relationship between DNA damage responses and pattern recognition of endogenous DNA and RNA in the cytoplasm. Project 2 tests hypotheses on how disruption in tissue architecture and mechanical forces result in chromosome missegregation and instability. It describes an approach to understand innate immune system recognition of this instability. Project 3 investigates in vivo responses to DNA damage within tumors, while designing rational approaches to enhance anti- tumor immune activation. Integration of these multidisciplinary projects with Mammalian Artificial Chromosome and Chemical Biology Cores will advance our primary goal of defining the molecular basis for immune detection of genome instability in cancer.