When Immune Cells Turn Bad-Tumor-Associated Microglia/Macrophages in Glioma

Abstract

As a substantial part of the brain tumor microenvironment (TME), glioma-associated microglia/macrophages (GAMs) have an emerging role in tumor progression and in controlling anti-tumor immune responses. We review challenges and improvements of cell models and highlight the contribution of this highly plastic cell population to an immunosuppressive TME, besides their well-known functional role regarding glioma cell invasion and angiogenesis. Finally, we summarize first therapeutic interventions to target GAMs and their effect on the immunobiology of gliomas, focusing on their interaction with T cells.

Keywords: GAMs; GBM; TME; glioblastoma; glioma; glioma-associated microglia/macrophages; microglia; tumor microenvironment.

Figure 1

Immunohistochemical staining of CD68 to visualize glioma-associated microglia/macrophages in primary glioblastoma tissue of GBM patient NCH3242. Scale bar 50 µm, magnification 10 µm.

Figure 2

Contribution of glioma-associated microglia/macrophages (GAMs) to a pro-tumorigenic tumor microenvironment (TME). Glioma-associated microglia/macrophages (GAMs) are recruited to the tumor lesion by several glioma cell-derived factors (pink: CCL2, CX3CL1, SDF-1, CSF-1, GM-CSF, GDNF, EGF), resulting in a polarization towards an anti-inflammatory and pro-tumorigenic M2-like phenotype. In the presence of glioma cells, GAMs express the IL-10 receptor and the cytokine itself. Therefore, the pro-tumorigenic M2-like phenotype can be sustained by autocrine IL-10 signaling. To study M2-like polarized GAMs, a combination of microglia/macrophage markers in general (green: CD11b, CD68, IBA1, and CX3CR1) and more M2-like specific markers (pink: CD163, CD204, CD206, and STAT3) are employed. Moreover, GAMs are endowed with a M2-associated secretome facilitating extracellular matrix (ECM) degradation (yellow: versican, antitrypsin, pentraxin 3, and several matrix metalloproteinases (MMPs)), and angiogenesis (red: VEGF, bFGF, IL-6, and IL-1β). Through the secretion of TGF-β, IL-6, IL-1β, EGF, STI-1, and IL-10 (violet), GAMs actively promote glioma cell proliferation, facilitate their invasion and migration, and impair immune cell functions.

Figure 3

Recruitment of glioma-associated microglia/macrophages (GAMs) by glioma cells through the secretion of soluble factors, such as CCL2 (violet), SDF-1 (pink), CSF-1 (blue), GM-CSF (green), and EGF (red).