Tumor derived adiponectin induces immunosuppressive macrophages in upper tract urothelial carcinoma

Upper tract urothelial carcinoma (UTUC) is a rare urologic cancer that is more aggressive and has a poorer survival rate compared to bladder cancer. Previously, we linked the UTUC derived factors with tumor-infiltrating immune cells. Macrophages are considered the most abundant immune cell population within tumors and serve as key regulators of the tumor microenvironment. This study aimed to investigate their role in modulating immunosuppression in UTUC tumors. Our results indicated that UTUC patients had higher proportion of M2-type macrophages in the periphery, and that tumor-infiltrating M2 macrophages were inversely correlated with tumor-infiltrating T lymphocytes within UTUC tumors. The supernatants from UTUC tumor tissue, as well as the predominant factor adiponectin, caused upregulation of arginase-1 and CD206 expression in THP-1 differentiated macrophages. Furthermore, macrophages treated with supernatants from UTUC tumor tissue or adiponectin alone inhibited CD4 T cell and CD8 T cell proliferation, along with reduction of effective cytokines produced by T cells. These results suggest that macrophages modulated by adiponectin are associated with T cell suppression in the UTUC tumor microenvironment, highlighting a potential therapeutic target.