title: Lack of IFN-gamma-mediated induction of the class II transactivator (CIITA) through promoter methylation is predominantly found in developmental tumor cell lines.
abstract: Downregulation of major histocompatibility complex (MHC) molecules by tumor cells impairs cellular immune recognition and contributes to inefficient cell-mediated tumor eradication. Low or lack of expression of MHC molecules is frequently observed in early developmental or embryonically derived tumor cells. Considering the central role of the class II transactivator (CIITA) in MHC class II- and class I-mediated antigen presentation, we compared the induction of CIITA by interferon-gamma (IFN-gamma) in a diverse panel of developmental and more differentiated tumor cell lines. In contrast to the more differentiated tumor cell lines, none of the developmental tumor cell lines were capable of expressing CIITA after treatment with IFN-gamma. Remarkably, in transient transfection assays, CIITA promoter IV (CIITA-PIV) was found to be induced by IFN-gamma. Southern blot analysis of genomic DNA obtained from the developmental tumor cell lines indicated that the absence of endogenous CIITA induction was due to methylation of the CIITA-PIV region. Exposure to 5-azacytidine restored induction of CIITA and congruent HLA-DRA expression in these cells. The observation that only developmental tumor cell lines, originating from various tissues, employ methylation to silence CIITA expression may reflect the natural status of CIITA expression during early development rather than oncogenic transformation.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: van der Stoep
authors.forename: Paula
authors.initials: P
authors.lastname: Biesta
authors.forename: Edwin
authors.initials: E
authors.lastname: Quinten
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van den Elsen
mesh_terms: D001374:Azacitidine / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000473:pathology; D002277:Carcinoma / Q000473:pathology; D002454:Cell Differentiation; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D005802:Genes, MHC Class II; D017930:Genes, Reporter; D006684:HLA-DR Antigens / Q000096:biosynthesis*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D006684:HLA-DR Antigens; C083728:MHC class II transactivator protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; D001374:Azacitidine