title: Human leukocyte antigen-G is frequently expressed in glioblastoma and may be induced in vitro by combined 5-aza-2'-deoxycytidine and interferon-γ treatments: results from a multicentric study.
abstract: Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex (MHC) class I molecule involved in immune tolerance processes, playing an important role in the maintenance of the semi-allogeneic fetus. Although HLA-G expression is restricted in normal tissues, it is broadly expressed in malignant tumors and may favor tumor immune escape. We analyzed HLA-G protein and mRNA expression in tumor samples from patients with glioblastoma collected in France, Denmark, and Brazil. We found HLA-G protein expression in 65 of 108 samples and mRNA in 20 of 21 samples. The absence of HLA-G protein expression was associated with a better long-term survival rate. The mechanisms underlying HLA-G gene expression were investigated in glioma cell lines U251MG, D247MG, and U138MG. Induction of HLA-G transcriptional activity was dependent of 5-aza-2'-deoxycytidine treatment and enhanced by interferon-γ. HLA-G protein expression was observed in U251MG cells only. These cells exhibited a permissive chromatin state at the HLA-G gene promoter and the highest levels of induced HLA-G transcriptional activity following 5-aza-2'-deoxycytidine treatment. Several antigen-presenting machinery components were up-regulated in U251MG cells after demethylating and IFN-γ treatments, suggesting an effect on the up-regulation of HLA-G cell surface expression. Therefore, because of its role in tumor tolerance, HLA-G found to be expressed in glioblastoma samples should be taken into consideration in clinical studies on the pathology and in the design of therapeutic strategies to prevent its expression in HLA-G-negative tumors.
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France.
authors.forename: Isabela J
authors.initials: IJ
authors.lastname: Wastowski
authors.forename: Renata T
authors.initials: RT
authors.lastname: Simões
authors.forename: Layale
authors.initials: L
authors.lastname: Yaghi
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Donadi
authors.forename: João T
authors.initials: JT
authors.lastname: Pancoto
authors.forename: Isabelle
authors.initials: I
authors.lastname: Poras
authors.forename: Emmanuèle
authors.initials: E
authors.lastname: Lechapt-Zalcman
authors.forename: Myriam
authors.initials: M
authors.lastname: Bernaudin
authors.forename: Samuel
authors.initials: S
authors.lastname: Valable
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Carlotti
authors.forename: Sébastien
authors.initials: S
authors.lastname: Flajollet
authors.forename: Stine S
authors.initials: SS
authors.lastname: Jensen
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
authors.forename: Bjarne W
authors.initials: BW
authors.lastname: Kristensen
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000368:Aged; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001706:Biopsy; D001932:Brain Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D000077209:Decitabine; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D059951:HLA-G Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016612:Paraffin Embedding; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016019:Survival Analysis; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D059951:HLA-G Antigens; D001613:beta 2-Microglobulin; D000077209:Decitabine; D007371:Interferon-gamma; D001374:Azacitidine