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Prostate cancer is the second most common cancer in men and the second leading cause of cancer-related deaths in men in the United States, with 191,930 men estimated to be diagnosed with prostate cancer and 33,330 patients expected to succumb to this disease in 2020 alone. Standard-of-care treatments, including active surveillance, surgery, radiation, and androgen deprivation therapy, provide positive clinical outcomes in patients with localized and regional disease. However, these strategies fail to effectively treat advanced prostate cancer, leading to a 5-year survival rate of 31% in patients with distant stage disease. Cancer immunotherapy has emerged as a powerful therapeutic strategy by enhancing the host immune response, particularly cytotoxic CD8+ T cells, to attack tumors. These strategies have proven successful in numerous cancers, such as melanoma, non-small cell lung cancer, and bladder cancer, however prostate cancer remains poorly responsive to these agents. The work presented in this dissertation demonstrates that the RON receptor tyrosine kinase, an oncogene implicated in the tumorigenesis of several epithelial cancers, is a critical regulator of the antitumor immune response in prostate cancer. Our studies herein identify novel RON-mediated communication networks between prostate tumor cells and immune cells as well as between different immune cell populations in the tumor microenvironment. We show that RON signaling in prostate epithelial cells and macrophages supports M2 macrophage activation and modulates the infiltration of multiple immune cell types with known roles in regulating prostate tumor growth and progression, such as CD4+ and CD8+ T cells. Importantly, our studies reveal that loss of RON signaling in macrophages promotes CD8+ T cell activation. Our deeper analyses show that the regulation of M2 macrophage activation by RON is in part through upregulation of RON expression in macrophages. Further, our preliminary data suggest that RON signaling in either prostate epithelial cells or in macrophages may trigger the activation of multiple pro-tumorigenic and immunosuppressive signaling pathways, including STAT3, AKT, and MAPK, potentially leading to the coordinated regulation of immunostimulatory and immunosuppressive molecule production. Specifically, our preliminary findings suggest that RON may enlist multiple soluble factors, such as HGFL and IL-33, to maintain macrophage RON expression and support M2 activation. Taken together, our work implicates that RON signaling directs multiple mechanisms involving cellular and secreted mediators to drive immunosuppression in prostate cancer, leading to resistance to immunotherapy. Thus, we provide strong rationale for the RON receptor as a promising immunotherapeutic target to overcome the shortcomings of current strategies and provide superior clinical outcomes in patients. |
