Immune biology of glioma-associated macrophages and microglia: functional and therapeutic implications

Abstract

CNS immune defenses are marshaled and dominated by brain resident macrophages and microglia, which are the innate immune sentinels and frontline host immune barriers against various pathogenic insults. These myeloid lineage cells are the predominant immune population in gliomas and can constitute up to 30-50% of the total cellular composition. Parenchymal microglial cells and recruited monocyte-derived macrophages from the periphery exhibit disease-specific phenotypic characteristics with spatial and temporal distinctions and are heterogeneous subpopulations based on their molecular signatures. A preponderance of myeloid over lymphoid lineage cells during CNS inflammation, including gliomas, is a contrasting feature of brain immunity relative to peripheral immunity. Herein we discuss glioma-associated macrophage and microglia immune biology in the context of their identity, molecular drivers of recruitment, nomenclature and functional paradoxes, therapeutic reprogramming and polarization strategies, relevant challenges, and our perspectives on therapeutic modulation.

Keywords: glioma; immune suppression; macrophages; microglia.

Fig. 1

Schematic demonstrating the cytokines for inducing polarized M1 versus M2 macrophages, markers used in their identification (oval), key transcriptional pathways that each uses (nucleus), metabolic preference (cytoplasm), and the elaborated immune effectors they secrete.

Fig. 2

Multiple major GAM chemokines are highly coexpressed in GBM and exhibit strong dual expression based on mRNA expression from TCGA. Pearson correlation analysis was used to evaluate the association of any 2 chemokines such as OPN, MCP1, LOX, CSF1, CXCL12, and POSTN. The number is the coefficient number r, and “**” or “ *** ” represents P < 0.01 or P < 0.001 associated to Pearson analysis.

Fig. 3

Kaplan–Meier survival analysis of glioma associated macrophage gene signatures performed at GlioVis data portal. The GlioVis analysis predicts prognostic outcomes in patients with low-grade glioma and GBM based on the differential gene expression and corresponding Kaplan–Meier survival analysis for (A) pan-microglia (TMEM119-left) and pan macrophage (CD68-right) markers; (B) M1 macrophage signatures: Trem1 (left) and NOS2 (right); and (C) M2 macrophage signatures; CD163 (left) and SOCS2 (right). Kaplan–Meier estimates of survival time of patients (x-axis) is plotted against the percentage of patients surviving (y-axis) from glioma datasets of TCGA. The data for survival have been directly extracted from the GlioVis Portal (without any computation on our side), available as a freeware accessible at http://gliovis.bioinfo.cnio.es/. Designations for high and low expression used in the survival analysis are based on the median of the target gene expression in all samples. Similar outcome results are obtained when patients are stratified based on glioma grade.

Fig. 4

(A) Multiplex immunohistochemical analysis of a GBM showing p-STAT3 expression (green) in CD3 T cells (blue) as they exit from the tumor vasculature that is lined with CD163 M2 macrophages (red). Glial fibrillary acidic protein (GFAP)+ glioma cells are shown in orange, and the nuclei are counterstained with 4′,6′-diamidino-2-phenylindole in blue (100 µm scale bar). (B) M2 macrophage (denoted in red) is directly interacting with a CD3 T cell (blue) that has p-STAT3 in its nucleus within the GBM microenvironment (50 µm scale bar).

Fig. 5

Summarized flow cytometry data of human monocytes that are polarized to the M0, M1, or M2 (n = 7) states and then profiled for expression of immune markers for which therapeutic modalities are available. The mean fluorescence intensity (MFI) of each designated immune marker was normalized to the associated isotype control. The mean is denoted by bold horizontal bars.