title: Macrophage migration inhibitory factor (MIF) expression in human malignant gliomas contributes to immune escape and tumour progression.
abstract: Macrophage migration inhibitory factor (MIF), which inhibits apoptosis and promotes angiogenesis, is expressed in cancers suppressing immune surveillance. Its biological role in human glioblastoma is, however, only poorly understood. We examined in-vivo expression of MIF in 166 gliomas and 23 normal control brains by immunohistochemistry. MIF immunoreactivity was enhanced in neoplastic astrocytes in WHO grade II glioma and increased significantly in higher tumour grades (III-IV). MIF expression was further assessed in 12 glioma cell lines in vitro. Quantitative RT-PCR showed that MIF mRNA expression was elevated up to 800-fold in malignant glioma cells compared with normal brain. This translated into high protein levels as assessed by immunoblotting of total cell lysates and by ELISA-based measurement of secreted MIF. Wild-type p53-retaining glioma cell lines expressed higher levels of MIF, which may be connected with the previously described role of MIF as a negative regulator of wild-type p53 signalling in tumour cells. Stable knockdown of MIF by shRNA in glioma cells significantly increased tumour cell susceptibility towards NK cell-mediated cytotoxicity. Furthermore, supernatant from mock-transfected cells, but not from MIF knockdown cells, induced downregulation of the activating immune receptor NKG2D on NK and CD8+ T cells. We thus propose that human glioma cell-derived MIF contributes to the immune escape of malignant gliomas by counteracting NK and cytotoxic T-cell-mediated tumour immune surveillance. Considering its further cell-intrinsic and extrinsic tumour-promoting effects and the availability of small molecule inhibitors, MIF seems to be a promising candidate for future glioma therapy.
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University, Heinrich-Hoffmann-Strasse 7, 60528, Frankfurt, Germany. michel.mittelbronn@kgu.de
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.forename: Pia
authors.initials: P
authors.lastname: Zeiner
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dombrowski
authors.forename: Brigitte
authors.initials: B
authors.lastname: Frank
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zachskorn
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Jörg
authors.initials: J
authors.lastname: Wischhusen
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000134:cerebrospinal fluid / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D055655:NK Cell Lectin-Like Receptor Subfamily K; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019139:Tumor Escape; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005904:Glial Fibrillary Acidic Protein; D008263:Macrophage Migration-Inhibitory Factors; D008869:Microtubule-Associated Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D020319:Oligodeoxyribonucleotides, Antisense; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C527085:KLRK1 protein, human; C489788:MAP2 protein, human