PROJECT 1: PROJECT SUMMARY Production of inflammatory cytokines and interferons by innate immune cells, within the tumor microenvironment, is a major determinant of tumor progression. Damage-associated molecular pattern (DAMP) recognizing receptors in myeloid cells are activated by ligands generated by the tumor cells, cytokines are induced locally and act upon the tumor cells to promote or impair their proliferation. Recent literature suggests that DNA and RNA are the major mediators of communication between the tumor cells and the innate immune cells. Our interests are in analyzing the biochemical pathways of signaling elicited by specific nucleic acid receptors in myeloid cells and investigating the effects of their manipulations in mouse models, which will be greatly facilitated by the newly generated TLR3, TLR9 and EGFR conditional knock-out mouse lines. We will test the hypothesis that the protein tyrosine kinase (PTK) activity of the epidermal growth factor receptor (EGFR) is essential for signaling by the two endosomal Toll-like receptors, TLR3 and TLR9, and by STING, the ER-bound mediator of cytoplasmic DNA signaling. Specifically, we will investigate the roles of EGFR and Src in TLR3 and TLR9 signaling by determining the biochemical requirements for TLR, EGFR and Src interactions to elicit signals. We will also identify the specific functions of EGFR and the adaptor protein, TRIF, in mediating STING-signaling and their contributions to STING-mediated protection from viral pathogenesis in mice will be evaluated. Finally, we will evaluate the role of EGFR-mediated cytokine production by myeloid cells in regulating tumor growth in three murine model systems: chemically induced skin and colon cancers and transplanted glioma. The above studies will illuminate the different mechanisms by which EGFR promotes signaling by three intracellular nucleic acid DAMP- recognizing receptors and thereby affects tumor growth.