Abstract 2656: Myeloid derived Wnt5a influences the immune-dynamics of melanoma tumor microenvironment

Abstract Despite breakthroughs in targeted therapies and immunotherapies, over 75% of patients either do not respond to therapy, or relapse. This may be due in part to changes in their tumor microenvironment (TME). Wnt5A is a glycoprotein that has been shown to influence melanoma phenotype, promoting a slow-cycling, but more invasive cancer. Wnt5A was thought to be produced from tumor cells and fibroblasts in the TME. However, our data now suggest that unique pathologically induced myeloid derived suppressor cells (MDSCs) produce a major proportion of Wnt5A in the TME which is taken up by melanoma cells to increase invasiveness. This finding highlights the diverse roles that MDSCs play in melanoma, going beyond immunosuppression. We created novel transgenic animals with MDSC specific knockdown of Wnt5A and demonstrate a clear decrease in the Wnt5A expression within the TME. Wnt5A deficient MDSCs caused an increase in CD8+ T-cells in peripheral blood and decreased tumoral MDSCs and Tregs. Tumor infiltrating lymphocytes also had significantly decreased PD-1 expression suggesting a less exhausted phenotype, and increased ratios of effector T-cells to immunosuppressive cells resulting in a more immunogenic TME. Wnt5A promotes a switch from proliferative to an invasive melanoma cell state. Myeloid specific Wnt5A knockdown caused decreased lung metastasis and significantly increased tumor growth in vivo, with the lack of MDSC infiltration negatively correlating to tumor volume. Tumor infiltrating MDSCs from control animals had a strong positive correlation with Tregs, whereas, this was completely ablated in animals with Wnt5A-negative MDSCs. Overall, our data suggests that while MDSCs contribute to an immunosuppressive and less immunogenic environment, they may have an additional function as the major source of Wnt5A in the tumor microenvironment. These two functions likely synergize to drive a highly metastatic and therapy-resistant phenotype altering immunogenicity. Citation Format: Stephen Douglass, Mitchell Fane, Emilio Sanseviero, Dmitry Gabrilovich, Ashani Weeraratna. Myeloid derived Wnt5a influences the immune-dynamics of melanoma tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2656.