ABSTRACT: This project proposes to develop a new Partnership for Aging and Cancer Research by bringing together NIH extra-mural and intra-mural investigators to collaboratively evaluate aging and the ovarian cancer (OvCa) microenvironment. Advanced age is a significant risk factor for OvCa incidence and negatively affects survival. We have demonstrated that immune system dysregulation is associated with aging, reflected by both increased myelopoiesis and decreased lymphopoiesis, such that immune cells exhibiting exhausted and over activated phenotypes are enhanced in aging. Additionally age-related changes in plasma exosome concentration and content differentially alter B cell activation. Furthermore, our pre-clinical studies have shown that aged mice develop consistently greater peritoneal tumor burden relative to young cohorts with concomitant changes in tumor immune cell composition and that pro-inflammatory signaling supports a pro-metastatic phenotype. Proposed experiments will test the hypothesis that host aging promotes OvCa metastatic progression through changes in the peritoneal proteome and through dysregulation of the peritoneal immune landscape. To address this hypothesis, Aim 1 will characterize age-related changes in the proteome (secreted, cell surface and intracellular) of tumor-naïve primary peritoneal mesothelial cells, examine age- associated alterations in the ascites proteome of tumor-bearing young vs aged mice, and assess the functional consequences of ascites-derived exosome-mediated information transfer to tumor cells and host peritoneal mesothelium. Complementary experiments in Aim 2 will characterize changes in the immune landscape of both host and tumor tissues in young vs aged mice, examine the contribution of aging peritoneal B1a lymphocytes to OvCa growth and assess the role of ascites-derived exosome-mediated information transfer to alterations in immune cell populations in the aged host. With successful completion of the studies proposed herein through this collaborative partnership, we will provide an unprecedented portrait of the aged ovarian tumor microenvironment (both tumor- and host-derived) to identify critical determinants of metastatic success for future mechanistic evaluation and therapeutic intervention.