title: Immune suppression and resistance mediated by constitutive activation of Wnt/β-catenin signaling in human melanoma cells.
abstract: Cancer-induced immunosuppression is a major problem reducing antitumor effects of immunotherapies, but its molecular mechanism has not been well understood. We evaluated immunosuppressive roles of activated Wnt/β-catenin pathways in human melanoma for dendritic cells (DCs) and CTLs. IL-10 expression was associated with β-catenin accumulation in human melanoma cell lines and tissues and was induced by direct β-catenin/TCF binding to the IL-10 promoter. Culture supernatants from β-catenin-accumulated melanoma have activities to impair DC maturation and to induce possible regulatory DCs. Those immunosuppressive culture supernatant activities were reduced by knocking down β-catenin in melanoma cells, partly owing to downregulation of IL-10. Murine splenic and tumor-infiltrating DCs obtained from nude mice implanted with human mutant β-catenin-overexpressed melanoma cells had less ability to activate T cells than did DCs from mice with control melanoma cells, showing in vivo suppression of DCs by activated Wnt/β-catenin signaling in human melanoma. This in vivo DC suppression was restored by the administration of a β-catenin inhibitor, PKF115-584. β-catenin-overexpressed melanoma inhibited IFN-γ production by melanoma-specific CTLs in an IL-10-independent manner and is more resistant to CTL lysis in vitro and in vivo. These results indicate that Wnt/β-catenin pathways in human melanoma may be involved in immunosuppression and immunoresistance in both induction and effector phases of antitumor immunoresponses partly through IL-10 production, and they may be attractive targets for restoring immunocompetence in patients with Wnt/β-catenin-activated melanoma.
authors: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Tomonori
authors: T
authors: Yaguchi
authors: Yasufumi
authors: Y
authors: Goto
authors: Kenji
authors: K
authors: Kido
authors: Hiroshi
authors: H
authors: Mochimaru
authors: Toshiharu
authors: T
authors: Sakurai
authors: Nobuo
authors: N
authors: Tsukamoto
authors: Chie
authors: C
authors: Kudo-Saito
authors: Tomonobu
authors: T
authors: Fujita
authors: Hidetoshi
authors: H
authors: Sumimoto
authors: Yutaka
authors: Y
authors: Kawakami
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation / Q000276:immunology; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics* / Q000276:immunology*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics*
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin