In Search for Reliable Markers of Glioma-Induced Polarization of Microglia

Abstract

Immune cells accumulating in the microenvironment of malignant tumors are tumor educated and contribute to its growth, progression, and evasion of antitumor immune responses. Glioblastoma (GBM), the common and most malignant primary brain tumor in adults, shows considerable accumulation of resident microglia and peripheral macrophages, and their polarization into tumor-supporting cells. There are controversies regarding a functional phenotype of glioma-associated microglia/macrophages (GAMs) due to a lack of consistent markers. Previous categorization of GAM polarization toward the M2 phenotype has been found inaccurate because of oversimplification of highly complex and heterogeneous responses. In this study, we characterized functional responses and gene expression in mouse and human microglial cultures exposed to fresh conditioned media [glioma-conditioned medium (GCM)] from human U87 and LN18 glioma cells. Functional analyses revealed mutual communication reflected by strong stimulation of glioma invasion by microglial cells and increased microglial phagocytosis after GCM treatment. To define transcriptomic markers of GCM-activated microglia, we performed selected and global gene expression analyses of stimulated microglial cells. We found activated pathways associated with immune evasion and TGF signaling. We performed computational comparison of the expression patterns of GAMs from human GBMs and rodent experimental gliomas to select genes consistently changed in different datasets. The analyses of marker genes in GAMs from different experimental models and clinical samples revealed only a small set of common genes, which reflects variegated responses in clinical and experimental settings. Tgm2 and Gpnmb were the only two genes common in the analyzed data sets. We discuss potential sources of the observed differences and stress a great need for definitive elucidation of a functional state of GAMs.

Circulating monocytes and tumor‐associated macrophages express recombined immunoglobulins in glioblastoma patients

“…Glioblastoma multiforme is the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular level [44]. In GBM, tumor-infiltrating microglia and peripheral macrophages are major immune cell populations within the tumor accounting for up to 30% of tumor mass in human GBMs [45]. In a recent study, we presented the expression of recombined immunoglobulin heavy and light chains in tumor-associated macrophages isolated from various types of tumor tissue [20].…”

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…Peripheral macrophages mostly appear in perivascular areas while resident macrophages are usually located in the peritumoral zone. A recent study showed that only a small batch of common genes toward species (rat, mice, human) differentiates GB-induced polarization of resident microglia (Walentynowicz et al, 2018). Although many studies tried to decipher the origin of TAMs in the tumor, no clear answer has yet been obtained.…”

Molecular interactions between tumor and its microenvironment in malignant gliomas

“…Transcriptomic analyses of CD11b+ cells isolated from human GBMs and rodent experimental gliomas showed a small overlap between their expression profiles [21,27,28]. Moreover, computational comparison of genes significantly changed in GAMs from different experimental models and clinical samples revealed only a small set of common genes [29]. This could be due many reasons: technical differences in cell isolation, a presence of mixed subpopulations of cells with different functions, inadequacy of animal models poorly reflecting human pathology or imprecise categorization of M1/M2 markers.…”

“…Although, these collected results are biased by differences in isolation procedure and cell identification criteria, the observed heterogeneity of responses may also result from co-existence of pro-and anti-inflammatory subsets of microglia and macrophages at specific phases of tumor evolution as well as dissimilar roles of microglia and peripherally recruited macrophages, which are yet to be understood [30,31]. Noteworthy, functional analysis on compared transcriptomic datasets from isolated GAMs shows similarities in upregulated cellular signaling pathways across all models [29]. It suggests that regardless of the observed differences, there is still an universal mechanism orchestrating polarization of microglia and macrophages within the tumor microenvironment.…”