Figure 2

PD-1 and its ligands are regulated by a complex network of factors. (A) PD-1 expression on T cells can be upregulated by numerous cytokines. Many of the common gamma chain cytokines (interleukin-2, IL-7, IL-15, IL-21) can upregulate PD-1. IL-6 and IL-12 through signal transducer and activator of transcription 3 (STAT3) and STAT4, respectively, enhance expression of PD-1 through distal regulatory elements. Of particular relevance to the tumor microenvironment, vascular endothelial growth factor A (VEGF-A) can upregulate PD-1 through a VEGF receptor found on T cells. The nuclear factors FoxO1 and NFATc1 upregulate PD-1 through its promoter. Blimp-1 and T-bet also interact with the promoter but block its expression. Blimp-1 also functions by inhibiting NFATc1 promoter-binding. (B) PD-L1 expression is also regulated by numerous mechanisms. Like PD-1, several of the common gamma chain cytokines upregulate it. IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) are also strong upregulators of both PD-L1 and PD-L2. In IFN-γ signaling, IRF-1 can bind to interferon response elements in the promoter of PD-L1. Hypoxia can lead to upregulation of HIF-α which binds to PD-L1’s promoter and stimulates expression. Mutations of the EGFR receptor and loss of PTEN in tumors can upregulate PD-L1. Another post-transcriptional mechanism of regulation is through micro RNAs. miR-200 suppression leads not only to cancer stage progression but also simultaneous upregulation of PD-L1. miR-513 can similarly regulate PD-L1 expression in biliary epithelial cells.