Abstract
Recent work has highlighted the tumor microenvironment as a central player in cancer. In particular, interactions between tumor and immune cells may help drive the development of brain tumors such as glioblastoma multiforme (GBM). Despite significant research into the molecular classification of glioblastoma, few studies have characterized in a comprehensive manner the immune infiltrate in situ and within different GBM subtypes.In this study, we use an unbiased, automated immunohistochemistry-based approach to determine the immune phenotype of the four GBM subtypes (classical, mesenchymal, neural and proneural) in a cohort of 98 patients. Tissue Micro Arrays (TMA) were stained for CD20 (B lymphocytes), CD5, CD3, CD4, CD8 (T lymphocytes), CD68 (microglia), and CD163 (bone marrow derived macrophages) antibodies. Using automated image analysis, the percentage of each immune population was calculated with respect to the total tumor cells. Mesenchymal GBMs displayed the highest percentage of microglia, macrophage, and lymphocyte infiltration. CD68+ and CD163+ cells were the most abundant cell populations in all four GBM subtypes, and a higher percentage of CD163+ cells was associated with a worse prognosis. We also compared our results to the relative composition of immune cell type infiltration (using RNA-seq data) across TCGA GBM tumors and validated our results obtained with immunohistochemistry with an external cohort and a different method. The results of this study offer a comprehensive analysis of the distribution and the infiltration of the immune components across the four commonly described GBM subgroups, setting the basis for a more detailed patient classification and new insights that may be used to better apply or design immunotherapies for GBM.
Highlights
There is a dynamic interaction between malignant and host cells within the tumor microenvironment, with host immune surveillance seeking to remove neoplasms and the tumor taking advantage of any opportunity to promote its own growth and progression
Hematoxylin and Eosin (H&E) stained slides were examined, and representative areas of different histology were selected to account for the heterogeneity observed in GBM samples with up to six cores for each tumor included in the Tissue Micro Arrays (TMA)
The natural role of the immune system against neoplasia, the immune compartment of the tumor tumor microenvironment (TME) is an appealing target for potential
Summary
There is a dynamic interaction between malignant and host cells within the tumor microenvironment, with host immune surveillance seeking to remove neoplasms and the tumor taking advantage of any opportunity to promote its own growth and progression. The tumor microenvironment (TME) resembles the environment within chronic inflammation, as cancer cells interact with pericytes, fibroblasts, and immune cells [25]. A three-step model of host-tumor interactions has been proposed, involving an “Elimination” phase, during which the host immune system tries to defeat the tumor, an “Equilibrium” phase whereby the host defense successfully controls tumor growth and curtails metastasis, and an “Escape” phase when tumor cells avoid surveillance to grow and spread freely [8]. Martinez-Lage et al Acta Neuropathologica Communications (2019) 7:203 composition of the tumor microenvironment is critical to understanding tumor progression and may provide insight on how to support the immune response and prevent evasion. GBM remains incurable, with a median overall survival of 12–15 months following diagnosis [1]
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