Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors

• Type of Material: Article
• Authors: Ioannis Kaffes, Emory University; Zhihong Chen, Emory University; Frank Szulzewsky, Fred Hutchinson Cancer Research Center; Cameron J. Herting, Emory University; Ben Gabanic, Emory University; Jose E. Velazquez Vega, Emory University; Jose Velazquez Vega, Emory University; Jeffrey M. Shelton, Emory University; Jeffrey Switchenko, Emory University; James L. Ross, Emory University; Leon F. McSwain, Emory University; Jason T. Huse, The University of Texas MD Anderson Cancer Center; Bengt Westermark, Uppsala University; Sven Nelander, Uppsala University; Karin Forsberg-Nilsson, Uppsala University; Lene Uhrbom, Uppsala University; Naga Prathyusha Maturi, Uppsala University; Patrick J. Cimino, Fred Hutchinson Cancer Research Center; Eric C. Holland, Fred Hutchinson Cancer Research Center; Helmut Kettenmann, Max Delbruck Center for Molecular Medicine; Camercon W. Brennan, Memorial Sloan Kettering Cancer Center; Daniel Brat, Emory University; Dolores Hambardzumyan, Emory University
• Language: English
• Date: 2019-08-23
• Publisher: Taylor and Francis Inc.
• Publication Version: Final Published Version
• Copyright Statement: © 2019, © 2019 The Author(s). Published by Taylor & Francis.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1080/2162402X.2019.1655360
• Title of Journal or Parent Work: Oncoimmunology
• Volume: 8
• Issue: 11
• Start Page: e1655360
• End Page: e1655360
• Grant/Funding Information: Moreover, research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292.
• Keywords: macrophage; subtype; Immunology; PD-L1 EXPRESSION; T cell; Life Sciences & Biomedicine; GLIOMA; TEMOZOLOMIDE; REGULATORY T-CELLS; SURVIVAL; PROGNOSTIC IMPACT; AIF1; MACROPHAGES; CANCER; MICROGLIA; SUBTYPES; Oncology; Glioblastoma; microenvironment; Science & Technology
• Research Categories: Health Sciences, Immunology

Abstract

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with a median survival of 14.6 months. Recent efforts have focused on identifying clinically relevant subgroups to improve our understanding of pathogenetic mechanisms and patient stratification. Concurrently, the role of immune cells in the tumor microenvironment has received increasing attention, especially T cells and tumor-associated macrophages (TAM). The latter are a mixed population of activated brain-resident microglia and infiltrating monocytes/monocyte-derived macrophages, both of which express ionized calcium-binding adapter molecule 1 (IBA1). This study investigated differences in immune cell subpopulations among distinct transcriptional subtypes of GBM. Human GBM samples were molecularly characterized and assigned to Proneural, Mesenchymal or Classical subtypes as defined by NanoString nCounter Technology. Subsequently, we performed and analyzed automated immunohistochemical stainings for TAM as well as specific T cell populations. The Mesenchymal subtype of GBM showed the highest presence of TAM, CD8+, CD3+ and FOXP3+ T cells, as compared to Proneural and Classical subtypes. High expression levels of the TAM-related gene AIF1, which encodes the TAM-specific protein IBA1, correlated with a worse prognosis in Proneural GBM, but conferred a survival benefit in Mesenchymal tumors. We used our data to construct a mathematical model that could reliably identify Mesenchymal GBM with high sensitivity using a combination of the aforementioned cell-specific IHC markers. In conclusion, we demonstrated that molecularly distinct GBM subtypes are characterized by profound differences in the composition of their immune microenvironment, which could potentially help to identify tumors amenable to immunotherapy.