title: FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer.
abstract: The limited success of cancer immunotherapy is often attributed to the loss of antigen-specific T cell function in situ. However, the mechanism for this loss of function is unknown. In this study, we describe a population of tumor-associated DCs (TADCs) in both human and mouse prostate cancer that tolerizes and induces suppressive activity in tumor-specific T cells. In tumors from human prostate cancer patients and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, TADCs expressed elevated levels of FOXO3 and Foxo3, respectively, which correlated with expression of suppressive genes that negatively regulate T cell function. Silencing FOXO3 and Foxo3 with siRNAs abrogated the ability of human and mouse TADCs, respectively, to tolerize and induce suppressive activity by T cells. Silencing Foxo3 in mouse TADCs was also associated with diminished expression of tolerogenic mediators, such as indoleamine-2,3-dioxygenase, arginase, and TGF-β, and upregulated expression of costimulatory molecules and proinflammatory cytokines. Importantly, transfer of tumor-specific CD4+ Th cells into TRAMP mice abrogated TADC tolerogenicity, which was associated with reduced Foxo3 expression. These findings demonstrate that FOXO3 may play a critical role in mediating TADC-induced immune suppression. Moreover, our results identify what we believe to be a novel target for preventing CTL tolerance and enhancing immune responses to cancer by modulating the immunosuppressive activity of TADCs found in the tumor microenvironment.
authors: Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
authors: Stephanie K
authors: SK
authors: Watkins
authors: Ziqiang
authors: Z
authors: Zhu
authors: Elena
authors: E
authors: Riboldi
authors: Kim A
authors: KA
authors: Shafer-Weaver
authors: Katherine E R
authors: KE
authors: Stagliano
authors: Martha M
authors: MM
authors: Sklavos
authors: Stefan
authors: S
authors: Ambs
authors: Hideo
authors: H
authors: Yagita
authors: Arthur A
authors: AA
authors: Hurwitz
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D034741:RNA, Small Interfering