Programmed death-1 and its ligands in immune responses of cancers

Programmed Death-1 (PD-1) is a type 1 transmembrane protein of immunoglobulin (Ig) superfamily. Along with its ligands (PD-L1 and PD-L2), it is a crucial checkpoint in the regulation of immuneresponses. PD-L1 is expressed in both tumor cells and tumor-infiltrating immune cells in tumor microenvironment and becomes elevated in response to inflammation. In addition, in the central nervous system, PD-L1 is expressed in inflammatory cells as well as vascular endothelial cells and astrocytes. However, inflammation increases the number of tumor-infiltrating lymphocytes and macrophages and enhances tumor growth, but inflammation prevents T-cell antitumor activity. On the other hand, the elevated expression of PD-L1 in tumor cells mediates tumor-induced T-cell exhaustion and subsequent immune suppression in inflammatory environments, which allows tumors to evade immune surveillance. In addition, treatment with pro-inflammatory cytokines such as tumor necrosis factor (TNFa), IL-6, IL-17 and interferons (type 1 and 2) are able to up-regulate PD-L1 in several cell lines including endothelial cells, epithelial cells, T and B cells as well as cancer cells. In breast cancer cells, inflammation induces macrophages to secrete inflammatory cytokines such as TNF-α that activate NF-κB signaling, allowing NF-kB to up-regulate COP9 signalosome 5 (CSN5) expression by binding to its promoter. CSN5 reduces PD-L1 ubiquitination and stabilizes it and promotes PD-L1 expression in response to inflammatory TNFα signaling. Successful therapeutic outcome directed against both anti-PD-L1 and anti-PD-1 antibodies in patients with advanced melanoma, non-small cell cancer and renal cell cancer, along with the notable role of this checkpoint pathway in the inflammatory tumor context, suggest that PD-L1/PD-1 blockade may provide an opportunity for therapeutic intervention based on the role of immune checkpoint pathways to treat cancers associated with inflammation

کلیدواژه ها:

Breast Cancer ، Cell and Cancer ، Solid Tumors ، Cancer Treatment and Management ، Targeted Cancer Therapy