Programmed cell death 1 (PD-1) is a costimulatory molecule that belongs to the CD28/CTLA-4 family. PD-1 recruits and activates an activation signaling pathway such as protein tyrosine phosphatase by binding to programmed cell death ligand 1 or 2 (PD-L1 or PD-L2). Abnormal PD-1/PD-L signaling can cause the immune microenvironment in the body to lose its steady state, leading to autoimmune diseases or tumors. PD-1 is an important factor in maintaining immune tolerance. Under physiological conditions, PD-1 recognizes antigen through T cell receptor (TCR), regulates the function of T cells in peripheral tissues, and regulates the body’s foreign antigen or autoantigen, an immune response that prevents the development of immune-related diseases. Different from traditional tumor treatments, PD-1/PD-L1 immune checkpoint inhibitors use the body’s own immune system to kill tumors, demonstrating excellent efficacy in a variety of solid tumors and hematological malignancies. The greatest advantage of these immune checkpoint inhibitors is their long-lasting response and long-term survival.
Figure 1 Mechanisms of programmed cell death protein 1 (PD1) signalling in T cells. ( Sharpe et al 2017)
PD-1 / PD-L1 signaling pathway
PD-L1 (B7-H1/CD273) and PD-L2 (B7-DC/CD274), the two ligands for PD-1, have similar effects. The main functions of both, inhibition of T cell receptor-mediated B cell proliferation and production of interleukin 2, 10, interferon gamma and other cytokines, are combined with PD-1 and lead to cell cycle arrest, thereby inhibiting T cell activation. Because PD-L1 is the main component of these two PD-1 ligands, the current research is mainly focused on PD-L1. PD-1 on the surface of activated T lymphocytes can specifically recognize PD-L1 on antigen-presenting cells (APC), thereby activating PD-1/PD-L1 pathway and attenuating the effects of Ras-MAPK and other pathways, which then leads to a decrease in the expression of three transcription factors, AP-1, NF-AT and NF-κB, causing an inhibition of T cell proliferation and differentiation, as well as the secretion of cytokines.
PD-1 and diseases
The expression of PD-1 is associated with the development and progression of various autoimmune diseases. Studies have shown that PD-1 knockout mice can elicit multiple autoimmune diseases. For example, PD-1 knockout mice with a C57BL/6 gene background develop lupus-like glomerulonephritis and lethal dilated cardiomyopathy. PD-1 signaling pathway is also involved in the progression of viral and microbial infectious diseases. Virus-specific cytotoxic T cells (CTLs) were found to be PD-1 positive in LCMV-infected mice, but were not found in the acute infection model. These PD-1 positive failing CTLs were found in patients with chronic HIV, HCV, and HBV infection. In addition, PD-1 expression was positively correlated with viral load.
Anti-PD-1 drug and its clinical application
(1) Nivolumab (Opdivo). A fully human IgG4 that can restore the immune effect of T lymphocytes during anti-tumor therapy is used to treat liver cancer, gastric cancer, metastatic non-small cell lung cancer, etc.
(2) Pembrolizumab (Keytruda). This humanized IgG4 was the first PD-1 monoclonal antibody marketed in the United States.
(3) Pidilizumab. A PD-1 humanized IgG-1κ monoclonal antibody is used to treat melanoma and recurrent follicular lymphoma.
(4) AMP-224. Developed for the treatment of advanced solid tumors, this PD-L2 IgG2a fusion protein causes an infusion reaction but no drug-related inflammatory adverse reactions clinically.
1. Longo, D. L. , & Boussiotis, V. A. . (2016). Molecular and biochemical aspects of the pd-1 checkpoint pathway.New England Journal of Medicine, 375(18), 1767-1778.
2. Liu, J. , Zhang, S. , Hu, Y. , Yang, Z. , & Lu, X. . (2016). Targeting pd-1 and tim-3 pathways to reverse cd8 t-cell exhaustion and enhance ex vivo t-cell responses to autologous dendritic/tumor vaccines.Journla of Immunotherapy, 39(4), 171-180.
3. Sharpe, A. H. , & Pauken, K. E. . (2017). The diverse functions of the pd1 inhibitory pathway. Nature Reviews Immunology.