Figure 3.

Hypoxia and immune checkpoint in glioma microenvironment. In immunosuppressive glioma microenvironment, despite the direct molecular and cellular mechanisms, the environmental factors, such as hypoxia and immune checkpoint, also play critical roles in the failure of immunosurveillance. (A) Compared with normal tissues, inner-glioma environment is always recognized as hypoxic and sufficient in immune cell infiltrations, due to the abnormalities in blood vessel morphology and impairing of BBB integrity. Upregulation of hypoxia-related factors, such as HIF-1α, cooperate with specific immune cells from leaky BBB to establish an immunosuppressive microenvironment and suppress the function of cytolytic T cells. (B) Under physiological condition, T cells can be activated through the engagement of MHC to TCR, together with the co-stimulatory signals, to recognize and lyse tumor cells. However, in glioma microenvironment, the elevated expression of CTLA-4 in immunosuppressive cells act as a competitive antagonist of the secondary activation signal, and further lead to the silencing of T cells. Furthermore, induced high expression of PD-1 on T cell surface, as well as PD-L1 on suppressive cells and tumor cells, lead to the anergy and apoptosis of T cells through ligand binding.