Abstract
Programmed cell death protein 1 (PD-1)/PD-ligand (L)1, the immune checkpoint inhibitors have emerged as a promising strategy for the treatment of various diseases including chronic liver diseases (CLDs) such as hepatitis, liver injury and hepatocellular carcinoma (HCC). The role of PD-1/PD-L1 has been widely inspected in the treatment of viral hepatitis and HCC. PD-1 is known to play a crucial role in inhibiting immunological responses and stimulates self-tolerance by regulating the T-cell activity. Further, it promotes apoptosis of antigen-specific T-cells while preventing apoptosis of Treg cells. PD-L1 is a trans-membrane protein which is recognized as a co-inhibitory factor of immunological responses. Both, PD-1 and PD-L1 function together to downregulate the proliferation of PD-1 positive cells, suppress the expression of cytokines and stimulate apoptosis. Owing to the importance of PD-1/PD-L1 signaling, this review aims to summarize the potential of PD-1/PD-L1 inhibitors in CLDs along with toxicities associated with them. We have enlisted some of the important roles of PD-1/PD-L1 in CLDs, the clinically approved products and the pipelines of drugs under clinical evaluation.
Highlights
Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule whose function is to reduce the T-cell activity for preventing autoimmune damage during immune responses
PD-1 transmits signals when it is linked to B-cell receptor (BCR) or T-cell receptors (TCR) and results in the formation of co-inhibitory microclusters with TCR and CD28 (Yearley et al, 2017)
The inhibitory immune checkpoint expression could be dysregulated in the tumor region, which results into the progression of T-cell mediated immune response via cancer immunotherapy
Summary
Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule whose function is to reduce the T-cell activity for preventing autoimmune damage during immune responses. In case of chronic infections, prolonged antigen exposure results in permanent expression of PD-1 which can limit immune-mediated clearance of pathogens (Ishida et al, 1992) It is mainly an immune checkpoint inhibitory receptor expressed on immune cells which are involved in activating immunosuppressive signaling cascade. When PD-1 ligands bind with PD-1, the phosphorylation of tyrosine of the cytoplasmic tail of PD-1 takes place which is followed by placement of Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP-2), which is a protein tyrosine phosphatase (PTP) (Riella et al, 2012) This functions by dephosphorylating kinases and in turn leads to inhibition of downstream signaling leading to the activation of T-cell receptors and CD28. It can lead to the dilation of cancer cells by interfering with the protective immune response (Han et al, 2020)
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