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Oncoimmunology. 2019 Aug 22;8(11):e1655360. doi: 10.1080/2162402X.2019.1655360. eCollection 2019.

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

Author information

1
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
2
Department of Cellular Neurosciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
3
Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
4
Discovery and Developmental Therapeutics Program, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
5
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
6
Department of Biostatistics and Bioinformatics, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
7
Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
9
Department of Pathology, University of Washington, Seattle, WA, USA.
10
Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
11
Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.

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.

KEYWORDS:

AIF1; Glioblastoma; T cell; macrophage; microenvironment; subtype

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