Modulation of Tumor Tolerance in Primary Central Nervous System Malignancies

Figure 2

Tumor cells and stromal elements with immune suppressive functions. CNS tumor cells, especially glioma cells, may develop the ability to secrete cytokines including IL6, IL10, and TGF-β and can take advantage of membrane integrin-bound metaloproteases (MMP2 and MMP9) to facilitate motility and invasiveness. Tumor-associated macrophages (TAMs) bind IL6 and IL10 via their respective receptors, leading to phosphorylation and activation of STAT3, a transcription factor that upregulates TAM IL6, IL10, and TGF-β production and secretion. Ligation of the CD200 receptor on microglia by the ligand found on parenchymal neurons downregulates inflammatory cytokine and nitric oxide production by microglial cells. Microglial cells also have low expression of MHC-II and secrete IL10 and TGF-β. Astrocytes excrete IL10, and also CCL21, thus recruiting activated T cells which are then educated to upregulate CTLA-4 to antagonize costimulatory signals. IL10 promotes CNS tumor growth and migration, whereas TGF-β is an important regulator of tumorigenesis, angiogenesis, and tumor cell motility and invasiveness.