title: MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape.
abstract: Malignant gliomas are intrinsic brain tumors with a dismal prognosis. They are well-adapted to hypoxic conditions and poorly immunogenic. NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DL). Here we evaluated the impact of miRNA on the expression of NKG2DL in glioma cells including stem-like glioma cells. Three of the candidate miRNA predicted to target NKG2DL were expressed in various glioma cell lines as well as in glioblastomas in vivo: miR-20a, miR-93 and miR-106b. LNA inhibitor-mediated miRNA silencing up-regulated cell surface NKG2DL expression, which translated into increased susceptibility to NK cell-mediated lysis. This effect was reversed by neutralizing NKG2D antibodies, confirming that enhanced lysis upon miRNA silencing was mediated through the NKG2D system. Hypoxia, a hallmark of glioblastomas in vivo, down-regulated the expression of NKG2DL on glioma cells, associated with reduced susceptibility to NK cell-mediated lysis. This process, however, was not mediated through any of the examined miRNA. Accordingly, both hypoxia and the expression of miRNA targeting NKG2DL may contribute to the immune evasion of glioma cells at the level of the NKG2D recognition pathway. Targeting miRNA may therefore represent a novel approach to increase the immunogenicity of glioblastoma.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Switzerland.
authors.forename: Paula
authors.initials: P
authors.lastname: Codo
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: Department of Biochemistry I, University of Regensburg, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Meister
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Switzerland.
authors.forename: Emese
authors.initials: E
authors.lastname: Szabo
authors.affiliation: Institute for Molecular Medicine, University of Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinle
authors.affiliation: Department of Neuropathology, Heinrich Heine University Düsseldorf and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Germany.
authors.forename: Marietta
authors.initials: M
authors.lastname: Wolter
authors.affiliation: Department of Neuropathology, Heinrich Heine University Düsseldorf and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D019139:Tumor Escape
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs