Programmed cell death-1 and its ligands: Current knowledge and possibilities in immunotherapy

The role of PD-1 signaling in health and immune-related diseases

“…PD-1 and its ligands play a vital role in inhibiting immune responses and promoting self-tolerance by modulating the activity of T-cells, inhibiting cytokine secretion, and inducing apoptosis ( 11 , 43 ). Inhibitors targeting the PD-1 pathway can rescue T cells from an exhausted state and revive the immune response against cancer cells ( 44 , 45 ). Based on these observations, the relationship between tumors and PD-1/PD-L1/PD-L2 has been studied widely, and PD-1/PD-L1-targeted inhibitors, as cancer immunotherapy, have been developed ( 11 , 13 , 17 , 29 , 44 – 46 ).…”

“…Inhibitors targeting the PD-1 pathway can rescue T cells from an exhausted state and revive the immune response against cancer cells ( 44 , 45 ). Based on these observations, the relationship between tumors and PD-1/PD-L1/PD-L2 has been studied widely, and PD-1/PD-L1-targeted inhibitors, as cancer immunotherapy, have been developed ( 11 , 13 , 17 , 29 , 44 – 46 ). Various pathways modulate the PD-1/PD-L1 axis in tumorigenesis, including the PI3K/AKT pathway, the MAPK pathway, the JAK/STAT pathway, the WNT pathway, the NF-κB pathway, and the Hedgehog (Hh) pathway ( 13 ).…”

“…Various pathways modulate the PD-1/PD-L1 axis in tumorigenesis, including the PI3K/AKT pathway, the MAPK pathway, the JAK/STAT pathway, the WNT pathway, the NF-κB pathway, and the Hedgehog (Hh) pathway ( 13 ). To date, several monoclonal antibodies targeting the PD-1/PD-L1 signaling pathway have obtained first- and later-line US Food and Drug Administration (FDA) approval in various solid and hematological malignancies, including non-small cell lung cancer, melanoma, renal cell carcinoma, urothelial carcinoma, gastric and gastroesophageal junction adenocarcinoma, head and neck squamous cell carcinoma, and others, in which response rates range from 15-30% (in most solid tumors) to 45–60% (in melanoma and microsatellite instability-high tumors) ( 44 , 47 ). Nivolumab (a fully human IgG4-blocking monoclonal antibody (mAb) against PD-1) was applied to the first-in-human trial of patients with advanced metastatic melanoma, colorectal cancer, castration-resistant prostate cancer, non-small cell lung cancer, and renal cell carcinoma in 2010, and first gained approval from the FDA to treat melanoma in 2014 ( 48 – 50 ).…”