title: Metastatic melanoma cells evade immune detection by silencing STAT1.
abstract: Transcriptional activation of major histocompatibility complex (MHC) I and II molecules by the cytokine, interferon γ (IFN-γ), is a key step in cell-mediated immunity against pathogens and tumors. Recent evidence suggests that suppression of MHC I and II expression on multiple tumor types plays important roles in tumor immunoevasion. One such tumor is malignant melanoma, a leading cause of skin cancer-related deaths. Despite growing awareness of MHC expression defects, the molecular mechanisms by which melanoma cells suppress MHC and escape from immune-mediated elimination remain unknown. Here, we analyze the dysregulation of the Janus kinase (JAK)/STAT pathway and its role in the suppression of MHC II in melanoma cell lines at the radial growth phase (RGP), the vertical growth phase (VGP) and the metastatic phase (MET). While RGP and VGP cells both express MHC II, MET cells lack not only MHC II, but also the critical transcription factors, interferon response factor (IRF) 1 and its upstream activator, signal transducer and activator of transcription 1 (STAT1). Suppression of STAT1 in vitro was also observed in patient tumor samples, suggesting STAT1 silencing as a global mechanism of MHC II suppression and immunoevasion.
authors.affiliation: Division of Cellular Biology and Immunology, Department of Biology, Georgia State University, Atlanta, GA 30303, USA. josborn1@gsu.edu.
authors.forename: JoDi Lynn
authors.initials: JL
authors.lastname: Osborn
authors.affiliation: Division of Cellular Biology and Immunology, Department of Biology, Georgia State University, Atlanta, GA 30303, USA. sgreer@gsu.edu.
authors.forename: Susanna F
authors.initials: SF
authors.lastname: Greer
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D000096743:Interferon gamma Receptor; D000096142:Cutaneous Malignant Melanoma
chemical_list: D014408:Biomarkers, Tumor; D000949:Histocompatibility Antigens Class II; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D053612:Janus Kinases; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor