FIGURE 2.

Depiction of the immunosuppressive environment in glioblastoma and current therapeutic approaches (red) to stimulate anti-tumor responses or inhibit suppressive immune cell populations. Glioma cells release chemoattractants and cytokines that recruit immune cells into the tumor microenvironment (TME). These factors elicit pro-tumor activities that inhibit effector T cells (Teff) and contribute to tumor progression. Glioma cells can also directly interact with immune cells and astrocytes impacting the effectiveness of chemotherapy. Inhibition of Stat3 by WP1066 reduces glioma-associated macrophages (GAM) by blocking intracellular signals induced by IL-10 to promote an anti-tumor macrophage (M1-like MΦ) phenotype. The CXCR4 antagonist AMD3100 prevents the binding of stromal cell-derived factor (SDF-1), resulting in decreased tumor proliferation and blocks the migration of myeloid-derived suppressor cells (MDSCs) in the TME. The CSF1R inhibitors (PLX3397, BLZ945) suppress the infiltration of myeloid cells (macrophages and MDSCs) within the TME. MDSCs synthesize prostaglandin E2 (PGE2) via COX-2 which inhibits effector T cells by reducing Interferon-gamma (IFN-γ) release. The COX-2 inhibitor, celecoxib reduces MDSC immunosuppressive activity. Interleukin-12 (IL-12) is secreted by antigen-presenting cells (APC) like dendritic cells and macrophages, exogenous IL-12 therapy triggers a pro-inflammatory transition of naïve T cells (ThO) to type 1 helper T cells (Th1) leading to an increase in IFN-y and tumor necrosis factor (TNF-α) secretion. Tumor cells express high levels of programmed cell death ligand (PD-L1) on their cell surface, which leads to exhausted T cells (Tex) by immune checkpoint signaling through their receptor programmed cell death protein 1 (PD-1). Inhibition of PD-1 with nivolumab reduces T cell exhaustion.