DNASE1L3 regulation of anti-tumor immune responses following radiation therapy

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Project Summary The critical preliminary data for this proposal relates to dendritic cells, a critical immune cell that links innate detection of infection to adaptive immune responses that can uniquely target and destroy targets. These same principles apply to initiate and control immune responses to cancer. We discovered that in tumors that are unable to generate adaptive immunity to assist in tumor cure following radiation therapy, dendritic cells fail to mature. These dendritic cells that fail to mature express a novel target gene called Dnase1l3, which has been shown to negatively regulate innate stimuli, and to negatively regulate autoimmune responses. This proposal is an innovative investigation into the role of this gene in anti-tumor immunity, and the mechanisms by which it is regulated in dendritic cells in tumors. We hypothesize that DNAse1l3 represses innate and adaptive immune responses in the tumor environment. The specific aims of this study are to 1: Determine the consequence of myeloid expression of Dnase1l3 on the immune response to radiation therapy; 2: Unbiased analysis of the consequence of myeloid expression of Dnase1l3 on the tumor immune environment following radiation therapy. Our study design incorporates CT- guided radiation therapy of multiple authentic pancreatic tumor models and using a range of RT doses and fractionations. These are combined with unique knockouts and assays that allow us to identify divergent responses in vitro and in vivo. Our analyses of clinical samples use high quality bioinformatic approaches that allow us to evaluate effect of the tumor environment on the biological response to innate adjuvants in patient samples.