Abstract A69: Elucidating the cell type-specific mechanisms of the Ron receptor in the prostate tumor microenvironment

Abstract

Abstract The incidence of advanced prostate cancer (PCa) in American men has grown by 72% within the last decade, yet current treatments fail to effectively treat advanced disease. We study the Ron receptor tyrosine kinase as a novel target for PCa treatment. Ron is primarily expressed in macrophages and epithelial cells and is found overexpressed in PCa. Ron expression increases with disease severity in humans and mouse models, suggesting Ron drives progression to advanced PCa. Our laboratory has shown that loss of Ron signaling in prostate epithelial cells or in myeloid cells markedly reduces prostate tumor growth and modulates the tumor microenvironment, particularly the functions of macrophages and CD8+ T cells. Thus, we hypothesize that the Ron receptor utilizes cell type-specific mechanisms to suppress the antitumor immune response. However, our previous studies were limited because they were performed separately in different orthotopic models. Therefore, we employed the well-established Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) PCa mouse model to study loss of Ron signaling in either cell type in a single autochthonous model. We used Cre-Lox technology to generate TRAMP mice containing conditional deletion of Ron signaling in prostate epithelial cells or in myeloid cells. At 30 weeks of age, prostate tumors are harvested and analyzed by weight, immunohistochemical staining, quantitative PCR, Western blot, and flow cytometry. To assess the effects of Ron modulation in each cell type and interrogate the interaction between tumor cells and macrophages, we perform in vitro co-culture assays utilizing an established prostate cancer epithelial cell line derived from the TRAMP model and bone marrow-derived macrophages. We observe that Ron signaling in either cell type is critical for prostate tumor growth in TRAMP mice. Furthermore, loss of Ron in either cell type leads to increased macrophage and CD8+ T-cell tumor infiltration, and our in vitro data show that loss of Ron in either cell type suppresses antitumor M1 macrophage activation and promotes tumor-supporting M2 macrophage activation. Additionally, preliminary data suggest loss of Ron in either cell type leads to increased activation of CD8+ tumor-infiltrating lymphocytes. Overall, our data suggest the Ron receptor coordinates immunosuppressive mechanisms in both the malignant tumor cells and the host macrophages to dampen antitumor immunity and promote prostate cancer. These studies implicate Ron targeting as a powerful therapeutic tool with broad utility for understanding and refining therapeutic strategies to treat advanced PCa. Citation Format: Camille Sullivan, Nicholas E. Brown, Susan E. Waltz. Elucidating the cell type-specific mechanisms of the Ron receptor in the prostate tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A69.