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Hiding in Plain Sight: Elucidation of mechanisms underlying metastatic melanoma immune escape via suppression of Major Histocompatability Complex (MHC) II through dysregulation of the JAK/STAT pathway
Author(s) -
Osborn joDi Lynn,
Greer Susanna F
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.929.6
Subject(s) - ciita , major histocompatibility complex , cancer research , biology , immunology , mhc class ii , mhc class i , immune system
Transcriptional activation of Major Histocompatability Complex (MHC) I and II molecules by the cytokine interferon gamma (IFN‐ γ) is a key step in cell‐mediated immunity against pathogens and tumors. Following IFN‐γ induction, JAK/STAT signaling triggers higher‐order chromatin remodeling and decondensation of the MHC locus, resulting in activation of MHC genes. Recent evidence suggests suppression of MHC I and II expression on multiple tumor types plays important roles in tumor immunoevasion. One such tumor is malignant melanoma, the leading cause of skin cancer related deaths. Despite awareness of MHC expression defects, the molecular mechanisms by which melanoma cells suppress MHC and escape from immune‐mediated destruction remain unknown. Here we analyze dysregulation of the JAK/STAT pathway and its role in suppression of MHC II in melanoma cell lines at the Radial Growth Phase (RGP), the Vertical Growth Phase (VGP) and the Metastatic Phase (MET). RGP and VGP cells express both MHC II and the MHC master regulator, the Class II Transactivator (CIITA). MET cells lack not only MHC II and CIITA, but also both protein and mRNA for STAT 1 and for the STAT 1 coactivator, the Interferon Response Factor (IRF) 1. The objective of this study is to elucidate the mechanisms underlying silencing of STAT1 in metastatic melanoma. Research supported by grants from the American Cancer Society (to S.F. Greer).