NDLI: Immune suppression and resistance mediated by constitutive activation of Wnt/ß-catenin signaling in human melanoma cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Sakurai, Toshiharu Yaguchi, Tomonori Goto, Yasufumi Mochimaru, Hiroshi Fujita, Tomonobu Kawakami, Yutaka Tsukamoto, Nobuo Kudo-Saito, Chie Sumimoto, Hidetoshi Kido, Kenji
Description	Country affiliation: Japan Author Affiliation: Yaguchi T ( Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.)
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/ß-catenin pathways in human melanoma for dendritic cells (DCs) and CTLs. IL-10 expression was associated with ß-catenin accumulation in human melanoma cell lines and tissues and was induced by direct ß-catenin/TCF binding to the IL-10 promoter. Culture supernatants from ß-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 ß-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 ß-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/ß-catenin signaling in human melanoma. This in vivo DC suppression was restored by the administration of a ß-catenin inhibitor, PKF115-584. ß-catenin-overexpressed melanoma inhibited IFN-Î³ 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/ß-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/ß-catenin-activated melanoma.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	5
Volume Number	189
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2012-09-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Immune Tolerance Melanoma Immunology Wnt Proteins Genetics Wnt Signaling Pathway Beta Catenin Animals Cells, Cultured Coculture Techniques Disease Resistance Hek293 Cells Hela Cells Lymphocytes, Tumor-infiltrating Metabolism Pathology Mice Mice, Inbred Balb C Mice, Nude Mice, Scid Mutation Neoplasm Transplantation Tumor Cells, Cultured Deficiency Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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