Astrocytic Regulation of Human Monocytic/Microglial Activation

Abstract

Recent reports have described reduced immunological responsiveness and stimulatory capacity among monocytes/microglia that infiltrate malignant human gliomas. Herein, we demonstrate that culture of ex vivo human monocytes or primary human microglia with tumor cells isolated from glioblastoma multiforme (GBM) specimens renders them tolerogenic, capable of suppressing the function of ex vivo monocytes in the absence of tumor cells or their soluble factors. We demonstrate that the tolerance induced in monocytes/microglia by GBM tumor cells is not associated with interference with the signaling cascade associated with TLR- or CD40-induced monocyte activation. Rather, these tumor cells appear to up-regulate pathways that antagonize positive signaling pathways, including but not limited to STAT3 and STAT5. Finally, we demonstrate that the tolerogenic properties of GBM tumor cells amplify properties inherent to nontransformed astrocytes. Future studies that identify all of the molecular mechanisms by which astrocytes and malignant gliomas suppress monocyte/microglial function will have dual therapeutic benefits: suppressing these pathways may benefit patients with astrocytic tumors, while enhancing them may benefit patients with autoimmune processes within the CNS, such as multiple sclerosis.

Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival

“…Ang-2 also has been shown to mediate the homing of Tie-2 + macrophages to human GBMs (15,16). In the tumor microenvironment, the macrophage population then is reprogrammed to a protumor (17)(18)(19), proangiogenic phenotype (20)(21)(22) in an Ang-2-dependent manner (22). Tumor-associated macrophages (TAMs) have a broad phenotypic spectrum, and their polarization can change in response to their microenvironment.…”

Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages

“…9,10 TAMs in the presence of glioma cells become immunosuppressive and elicit an anti-inflammatory response by increasing the expression and release of cytokines such as IL-10 and VEGF, thereby contributing to a milieu that promotes the survival and growth of the glioblastoma cells. 8,11,12 Microglia express functional glutamate receptors, 13,14 and microglia as well as macrophages are capable of inducing expression of glutamate transporters and glutamine synthetase in neuropathological conditions, 15 suggesting a functional role of microglia and macrophages in glutamate signaling. However, little is known about the role of TAMs in response to the dysregulation of glutamate signaling in a glioblastoma microenvironment.…”

Perivascular niches as points of the utmost expression of tumor microenvironment

“…Reactive astrocytes are known not only to participate in BBB function with their end-feet, but also to favor tumor cell invasiveness [44][45][46]. However, in infiltrating tumor their cell bodies remain distant from vessels, whereas their end-feet on them mostly disappear with advancing cell invasion.…”