title: CD200 is induced by ERK and is a potential therapeutic target in melanoma.
abstract: Immune-mediated antitumor responses occur in patients with metastatic melanoma (MM), and therapies designed to augment such responses are clinically beneficial. Despite the immunogenicity of melanoma, immunomodulatory therapies fail in the majority of patients with MM. An inability of DCs to sufficiently activate effector cells may, in part, underlie this failure of the antitumor response seen in most patients. In this work, we show that mutation of N-RAS or B-RAF, signature genetic lesions present in most MMs, potently induced the expression of cell-surface CD200, a repressor of DC function. Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. CD200 mRNA expression correlated with progression and was higher in melanoma than in other solid tumors or acute leukemia. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect. These data indicate that in addition to its effects on growth, survival, and motility, ERK activation in MM attenuates a host antitumor immune response, implicating CD200 and its interaction with the CD200 receptor as a potential therapeutic target for MM.
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7295, USA.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Petermann
authors.forename: Gabriela I
authors.initials: GI
authors.lastname: Rozenberg
authors.forename: Daniel
authors.initials: D
authors.lastname: Zedek
authors.forename: Pamela
authors.initials: P
authors.lastname: Groben
authors.forename: Karen
authors.initials: K
authors.lastname: McKinnon
authors.forename: Christin
authors.initials: C
authors.lastname: Buehler
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.forename: Janiel M
authors.initials: JM
authors.lastname: Shields
authors.forename: Shannon
authors.initials: S
authors.lastname: Penland
authors.forename: James E
authors.initials: JE
authors.lastname: Bear
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Thomas
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
mesh_terms: D000208:Acute Disease; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D064446:Orexin Receptors; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000276:immunology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; C477337:CD200R1 protein, human; D064446:Orexin Receptors; D011956:Receptors, Cell Surface; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); C042739:antigens, CD200