Immune landscapes associated with different glioblastoma molecular subtypes

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.

Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature.

“…Notably, the expression of PN or MES markers did not allow us to distinguish between these two immune subtypes of GBMs. These results differ from some computational [7] and IHC [9,10] studies, showing the enrichment of myeloid and lymphoid cells in the MES subtype. Another study, however, observed an accumulation of CL tumors among GBMs with a high immune in ltrate [8].…”

“…Nonetheless, gliomas are far from being a homogenous entity and disparities in their immune content might also condition their response to different therapeutic strategies. In order to classify the immunological pro le of glial tumors, several groups have used computational and immunohistochemical (IHC) analysis approaches [7][8][9][10]. Here, we have performed a comprehensive characterization of the tumors by ow cytometry.…”

Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature

“…In order to classify the immunological profile of glial tumors, several groups have used computational and immunohistochemical analysis approaches [7][8][9][10] . However, immune cell types are heterogeneous at the level of ontogeny, spatial distribution and functionality within the tumor immune compartment.…”

Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment

“…TAMs are recruited to the glioma and produce cytokines and other factors that promote glioma cells proliferation and migration. [ 38 ] Recently, Martinez‐Lage et al carried out a comprehensive immunohistochemical study to characterize the immune landscape associated with the four GBM molecular subtypes defined by Verhaak et al [ 39 ] They found that the most immunogenic subtype was the mesenchymal subtype, followed by neural, classical, and proneural GBMs. They also determined that medium and high levels of CD163 + macrophage lineage is correlated to patients' survival, with medium levels of infiltration having a worse impact in survival than high levels.…”