Identification of FOXO3A as a regulator of dendritic cell tolerogenicity in human and murine prostate cancer (165.22)

Abstract

Abstract The limited success of cancer immunotherapies is often attributed to the loss of antigen-specific T cell function in situ. In this study, we demonstrate a novel mechanism of tolerance induction by tumor-associated dendritic cells (TADCs) in human and mouse prostate cancer. TADCs from human prostate cancer patients and TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice expressed elevated levels of FOXO3A which correlated with expression of suppressive genes that negatively regulate T cell function. Similar results were observed in both a B16 melanoma and a RENCA renal cell carcinoma model. Furthermore, TADC isolated from tumors in Foxo3a-/- mice had reduced tolerogenic function. Additionally, silencing Foxo3a with siRNAs abrogated the ability of TADCs to tolerize and induce suppressive activity by T cells. This was associated with diminished expression of tolerogenic mediators, indoleamine-2,3-dioxygenase, arginase, and TGF-beta and up-regulated expression of co-stimulatory molecules and pro-inflammatory cytokines. In TRAMP mice, provision of tumor-specific CD4+ T cell help abrogated TADC tolerogenicity which was associated with reduced FOXO3A expression. These findings demonstrate that FOXO3A plays a critical role in mediating TADC-induced immune suppression. Moreover, our results identify a novel target for preventing CTL tolerance and enhancing immune responses to cancer by modulating the immunosuppressive activity of TADC found in the tumor microenvironment.