title: MIF Receptor CD74 is Restricted to Microglia/Macrophages, Associated with a M1-Polarized Immune Milieu and Prolonged Patient Survival in Gliomas.
abstract: The macrophage migration inhibitory factor (MIF) receptor CD74 is overexpressed in various neoplasms, mainly in hematologic tumors, and currently investigated in clinical studies. CD74 is quickly internalized and recycles after antibody binding, therefore it constitutes an attractive target for antibody-based treatment strategies. CD74 has been further described as one of the most up-regulated molecules in human glioblastomas. To assess the potential relevance for anti-CD74 treatment, we determined the cellular source and clinicopathologic relevance of CD74 expression in human gliomas by immunohistochemistry, immunofluorescence, immunoblotting, cell sorting analysis and quantitative polymerase chain reaction (qPCR). Furthermore, we fractionated glioblastoma cells and glioma-associated microglia/macrophages (GAMs) from primary tumors and compared CD74 expression in cellular fractions with whole tumor lysates. Our results show that CD74 is restricted to GAMs in vivo, while being absent in tumor cells, the latter strongly expressing its ligand MIF. Most interestingly, a higher amount of CD74-positive GAMs was associated with beneficial patient survival constituting an independent prognostic parameter and with an anti-tumoral M1 polarization. In summary, CD74 expression in human gliomas is restricted to GAMs and positively associated with patient survival. In conclusion, CD74 represents a positive prognostic marker most probably because of its association with an M1-polarized immune milieu in high-grade gliomas.
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Pia S
authors.initials: PS
authors.lastname: Zeiner
authors.affiliation: Department of Neuropathology, Charité, Berlin, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Preusse
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Anna-Eva
authors.initials: AE
authors.lastname: Blank
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zachskorn
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany.|Department of Neurosurgery, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Baumgarten
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Lixi
authors.initials: L
authors.lastname: Caspary
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Braczynski
authors.affiliation: Department of Experimental Neurosurgery, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Weissenberger
authors.affiliation: Institute of Forensic Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Hansjürgen
authors.initials: H
authors.lastname: Bratzke
authors.affiliation: Miltenyi Biotec, Bergisch Gladbach, Germany.
authors.forename: Sandy
authors.initials: S
authors.lastname: Reiß
authors.affiliation: Miltenyi Biotec, Bergisch Gladbach, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pennartz
authors.affiliation: Senckenberg Institute of Pathology, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Ria
authors.initials: R
authors.lastname: Winkelmann
authors.affiliation: Department of Experimental Neurosurgery, Goethe University Frankfurt, Frankfurt am Main, Germany.|Department of Neurosurgery, Goethe University Frankfurt, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Senft
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.affiliation: Junior Research Group "Tumour Progression and Immune Escape", Interdisciplinary Center for Clinical Research, Department for Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Wischhusen
authors.affiliation: Department of Neuropathology, Charité, Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Edinger Institute, Institute of Neurology, Goethe University Frankfurt, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D046228:Microarray Analysis; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C112986:AIF1 protein, human; D051928:CD47 Antigen; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D012333:RNA, Messenger
keywords: CD74; MIF; glioma; immune polarization