Programmed cell death protein 1 (PD1), also known as CD279, is an inhibitory receptor that is expressed by all T cells during activation. It regulates T cell effector functions during various physiological responses, including acute and chronic infection, cancer and autoimmunity, and in immune homeostasis.
PD1 often shows high and sustained expression levels during persistent antigen encounter, which can occur in the setting of chronic infections and cancer. In these settings, PD1 can limit protective immunity.
PD1 limits the activation and function of potentially pathogenic self-reactive CD4+ and CD8+ T cells, and PD-L1 can shield target organs from autoimmune attack.
PD-1’s ligands, PD-L1 and PD-L2, are commonly expressed on the surface of dendritic cells or macrophages. PD-1 and PD-L1/PD-L2 belong to the family of immune checkpoint proteins that act as co-inhibitory factors that can halt or limit the development of the T cell response. The PD-1/PD-L1 interaction ensures that the immune system is activated only at the appropriate time in order to minimize the possibility of chronic autoimmune inflammation.
Under normal conditions, the immune system performs a series of steps which lead to an anticancer immune response and cancer cell death, known as the cancer immunity cycle:
The PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism that is exerted by tumor cells in response to endogenous immune anti-tumor activity. PD-L1 is commonly over expressed on tumor cells or on non-transformed cells in the tumor microenvironment. PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated T cells, which leads to the inhibition of the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
Monoclonal antibody therapies against PD-1 and PD-L1 are being routinely used including Nivolumab, an anti-PD-1 drug developed by Bristol-Myers Squibb, which is approved for previously treated metastatic melanoma and squamous non-small cell lung cancer; and Pembrolizumab, developed by Merck and approved for previously treated metastatic melanoma. There are several other immunotherapies associated with PD-1/PD-K1 under development.
The efficiency of the immune checkpoint blockade with monoclonal antibodies in cancer treatment is remarkable, but not all patients respond to a single therapy. To enhance and broaden the anti-tumor activity of immune checkpoint inhibition the next step is combining agents with synergistic mechanisms of action. An example of this is the success of the combination of PD-1/PD-L1 inhibition blockage with complementary checkpoint inhibitor CTLA-4 in melanoma and non-small cell lung cancer.
EUPROTEIN has developed and validated PD-1 and PD-L1 protein that could be potentially used in the discovery and development of new cancer immunotherapies. These high-quality proteins might also be applied in future development of diagnostic and progressive assays involved the PD-1/PD-L1 pathway.
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