New immunotherapies targeting the PD-1 pathway

Abstract

Ligands from the B7 family bind to receptors of the CD28 family, which regulate early T cell activation in lymphoid organs and control inflammation and autoimmunity in peripheral tissues. Programmed death-1 (PD-1), a member of the CD28 family, is an inhibitory receptor on T cells and is responsible for their dysfunction in infectious diseases and cancers. The complex mechanisms controlling the expression and signaling of PD-1 and programmed death ligand 1 (PD-L1) are emerging. Recently completed and ongoing clinical trials that target these molecules have shown remarkable success by generating durable clinical responses in some cancer patients. In chronic viral infections, preclinical data reveal that targeting PD-1 and its ligands can improve T cell responses and virus clearance. There is also promise in stimulating this pathway for the treatment of autoimmune and inflammatory disorders.

Keywords: PD-1; PD-L1; PD-L2; cancer; immunotherapy; viral infection.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. PD-1 signaling

PD-1 has both an intracellular immunoreceptor tyrosine-based switch motif (ITSM) and immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail. SHP-2 can bind to the phosphorylated ITSM. PD-1 ligation by ligands leads to overall inhibition of TCR signaling through inhibition of CD3ζ chain phosphorylation and Zap-70 association. PD-1 signaling causes the downregulation of both Ras and Bcl-xL which affect proliferation and cell survival, respectively. An increase in BATF can be seen which impairs the effector function of T cells. PD-1 also inhibits the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by inhibiting the activation of PI3K. This has downstream effects including the downregulation of mechanistic target of rapamycin (mTOR) and an increased half-life of FoxO1. PD-1 signaling also influences the cell’s metabolism by inhibiting glycolysis and promoting fatty acid oxidation. Together, all of these effects cause T cells to become less proliferative, lose their effector functions, and take on an exhausted and dysfunctional phenotype. The net effect of PD-1 ligation on all of these processes is shown in red with arrow direction indicating upregulation and downregulation.

Figure 2. Regulation of PD-1 and PD-L1 expression

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.