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: Pia S Zeiner, Corinna Preusse, Anna-Eva Blank, Cornelia Zachskorn, Peter Baumgarten, Lixi Caspary, Anne K Braczynski, Jakob Weissenberger, Hansjürgen Bratzke, Sandy Reiß, Sandra Pennartz, Ria Winkelmann, Christian Senft, Karl H Plate, Jörg Wischhusen, Werner Stenzel, Patrick N Harter, Michel Mittelbronn
• Journal: Brain pathology (Zurich, Switzerland) (Brain Pathol) Vol. 25 Issue 4 Pg. 491-504 (Jul 2015) ISSN: 1750-3639 [Electronic] Switzerland
• PMID: 25175718 (Publication Type: Journal Article)
• Copyright: © 2014 International Society of Neuropathology.

Chemical References

• AIF1 protein, human
• CD47 Antigen
• Calcium-Binding Proteins
• DNA-Binding Proteins
• Glial Fibrillary Acidic Protein
• Microfilament Proteins
• RNA, Messenger

Topics

• Brain Neoplasms (metabolism, mortality, pathology)
• CD47 Antigen (genetics, metabolism)
• Calcium-Binding Proteins
• Cell Line, Tumor
• DNA-Binding Proteins (metabolism)
• Female
• Flow Cytometry
• Glial Fibrillary Acidic Protein (metabolism)
• Glioma (metabolism, mortality, pathology)
• Humans
• Kaplan-Meier Estimate
• Macrophages (metabolism)
• Male
• Microarray Analysis
• Microfilament Proteins
• Microglia (metabolism)
• RNA, Messenger (metabolism)
• Up-Regulation (physiology)