Friends with Benefits: Chemokines, Glioblastoma-Associated Microglia/Macrophages, and Tumor Microenvironment

Abstract

Glioma is the most common primary intracranial tumor and has the greatest prevalence of all brain tumors. Treatment resistance and tumor recurrence in GBM are mostly explained by considerable alterations within the tumor microenvironment, as well as extraordinary cellular and molecular heterogeneity. Soluble factors, extracellular matrix components, tissue-resident cell types, resident or newly recruited immune cells together make up the GBM microenvironment. Regardless of many immune cells, a profound state of tumor immunosuppression is supported and developed, posing a considerable hurdle to cancer cells' immune-mediated destruction. Several studies have suggested that various GBM subtypes present different modifications in their microenvironment, although the importance of the microenvironment in treatment response has yet to be determined. Understanding the microenvironment and how it changes after therapies is critical because it can influence the remaining invasive GSCs and lead to recurrence. This review article sheds light on the various components of the GBM microenvironment and their roles in tumoral development, as well as immune-related biological processes that support the interconnection/interrelationship between different cell types. Also, we summarize the current understanding of the modulation of soluble factors and highlight the dysregulated inflammatory chemokine/specific receptors cascades/networks and their significance in tumorigenesis, cancer-related inflammation, and metastasis.

Keywords: chemokine; dendritic cells; gene editing; glioblastoma; glioblastoma-associated macrophages; glioblastoma-associated microglia; myeloid-derived suppressor cells; soluble factors; specific receptors; tumor infiltrating lymphocytes; tumor microenvironment.

Figure 1

Immune cells types of tumor microenvironment of GBM. The illustration was created with Bioreder.com.

Figure 2

Tumor microenvironment of GBM. The figure depicts immune cells and non-immune cells that have been reported to be associated with tumor cells in TME and their bidirectional crosstalk: tumor-associated macrophages (TAMs—microglia and peripheral monocytes), dendritic cells: cDC1 cDC2 , plasmacytoid DCs, myeloid-derived suppressor cells (MDSCs), tumor-associated neutrophils (TANs). Illustration created with Bioreder.com.

Figure 3

The most important chemokines (CXCL) and their specific receptors (CXCR) axis involved in glioma development. The colored nodes are represented by query chemokines and the first shell of interactors. Edges represent protein-protein functional associations, assigned with different color codes, as follows: a blue edge indicates known interactions from curated databases, a pink edge indicates known interactions that have been experimentally determined, a green edge indicates predicted interactions in the gene neighborhood, a red edge indicates predicted interactions for gene fusions, a blue-ink edge indicates predicted interactions for gene co-occurrences, a light-green edge indicates other interactions derived from text mining, a black edge indicates coexpression, and light-blue indicates other interactions derived from protein homology. Abbreviations: ACKR3—CXCR7. Image created with String-database (https://string-db.org/, accessed on 5 January 2022).