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.
| Original language | English (US) |
|---|---|
| Article number | e1655360 |
| Journal | OncoImmunology |
| Volume | 8 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2 2019 |
Funding
The authors would like to thank Dr. Suresh Mohla for the inspiration to initiate the project and his active involvement during the entire process. We would also like to thank the Tumor Microenvironment Network at the National Cancer Institute for providing antibodies for this study. Furthermore, the authors extend their thanks to Neil Anthony for his advice on image quantification, Victor Maximov for fruitful discussions, and Kristina Alikhanyan for technical assistance. The graphic illustrations of immune cells were created by Dave Schumick. This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core of the Emory+Children’s Pediatric Research Center. 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The study was financially supported by funds from National Institutes of Health [R01CA176659];Swedish Cancer Society [110363];Swedish Cancer Society [140385];Swedish Cancer Society [130500];Swedish Research Council [521-2013-3356];Berlin Institute of Health;German Research Foundation [DFG SZ 350/1-1];German Academic Exchange Service;National Institutes of Health (US) [R01NS100864];National Institutes of Health (US) [F31NS106887];National Institutes of Health (US) [F31CA232531];National Institutes of Health (US) [U01CA160882];National Institutes of Health (US) [4T32GM008602-20]. The authors would like to thank Dr. Suresh Mohla for the inspiration to initiate the project and his active involvement during the entire process. We would also like to thank the Tumor Microenvironment Network at the National Cancer Institute for providing antibodies for this study. Furthermore, the authors extend their thanks to Neil Anthony for his advice on image quantification, Victor Maximov for fruitful discussions, and Kristina Alikhanyan for technical assistance. The graphic illustrations of immune cells were created by Dave Schumick. This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core of the Emory+Children’s Pediatric Research Center. 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Keywords
- AIF1
- Glioblastoma
- T cell
- macrophage
- microenvironment
- subtype
ASJC Scopus subject areas
- Oncology
- Immunology and Allergy
- Immunology