Interdependencies of the Neuronal, Immune and Tumor Microenvironment in Gliomas

Abstract

Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes.

Keywords: astrocytoma; glioblastoma; glioma; immune microenvironment; tumor microenvironment.

Figure 1

The four GBM molecular subtypes are proneural, neural, classical, and mesenchymal.

Figure 2

Both PI3K and Ras pathways, triggered by Receptor Tyrosine Kinases (RTKs), facilitate the recruitment of myeloid populations into tumor microenvironment, where they are polarized into pro-tumor populations.

Figure 3

2-Hydroxygluterate produced by IDH1/2-mutant tumors may be able to evade immunity by downregulating MHC II and CD80/CD86 expression on APCs and downregulating NKG2D Ligands on the surface of tumor cells.

Figure 4

Tumor (glioblastoma) Neuronal Interactions.