Programmed cell death protein 1 , also known as PD-1 and CD279 (the differentiation group 279), is a cell surface receptor that plays an important role in lowering the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. PD-1 is an immune checkpoint and guard against autoimmunity through a dual mechanism to promote apoptosis (programmed cell death) in antigen-specific T-cells in the lymph nodes while simultaneously reduces apoptosis in T regulator cells (anti-inflammatory, suppressor T cells).
Through this mechanism, PD-1 inhibits the immune system. It prevents autoimmune diseases, but also can prevent the immune system from killing cancer cells.
New-class drugs that block PD-1, PD-1 inhibitors , activate the immune system to attack tumors and are therefore used with varying efficacy to treat some cancers.
The human PD-1 protein is encoded by the PDCD1 genes. PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 binds two ligands, PD-L1 and PD-L2.
Video Programmed cell death protein 1
Structure
Programmed death 1 is a type I membrane protein of 268 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators. The protein structure includes the extracellular IgV domain followed by transmembrane and intracellular tails. Intracellular tails contain two phosphorylation sites located within the immunoreceptor-based tyrosine inhibitory motif and thyroid-based thyrosine immunoreceptor screw motif, suggesting that PD-1 negatively regulates TCR signals of T-cell receptors. This is consistent with the binding of SHP-1 and SHP-2 phosphatase to the PD-1 cytoplasm of the ligand binding. In addition, PD-1 ligation also regulates E3-ubiquitin ligases CBL-b and c-CBL which trigger down-modulated T cell receptors. PD-1 is expressed on the surface of activated T cells, B cells, and macrophages, suggesting that compared with CTLA-4, wider PD-1 negatively regulates the immune response.
Maps Programmed cell death protein 1
Ligans
PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family. The PD-L1 proteins are regulated in macrophages and dendritic cells (DCs) in response to LPS and GM-CSF treatments, and in T cells and B cells on TCR and B cell receptor signaling, whereas in resting mice PD-L1 mRNA can be detected in the heart, lungs, thymus, spleen, and kidney. PD-L1 is expressed in almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma after treatment with IFN-. PD-L2 expression is more limited and expressed mainly by DC and some tumor lines.
Function
Several lines of evidence suggest that PD-1 and its ligand negatively regulate the immune response. PD-1 knockout mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy in C57BL/6 and BALB/c backgrounds, respectively. In vitro, anti-CD3 treatment stimulates T cells with PD-L1-Ig resulting in lower T-cell proliferation and IFN-? secretions. IFN-? is a key pro-inflammatory cytokine that increases T cell inflammatory activity. The reduction of T cell proliferation also correlates with attenuated IL-2 secretion and together, this data suggests that PD-1 negatively regulates T cell responses.
Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4 and CD8 T cells showed that CD8 T cells were more susceptible to inhibition by PD-L1, although this may depend on the strength of TCR signaling. Consistent with the negative role in regulating the CD8 T cell response , using the LCMV virus vector model of chronic infection, the Rafi Ahmed group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition. a specific CD8 cell effector function T, which can be reversed by blocking the PD-1-PD-L1 interaction.
Because CTLA-4 negatively regulates anti-tumor immune responses, the closely related molecules of PD-1 have been explored independently as targets for immunotherapy. PD-L1 expression in tumor cells inhibits anti-tumor activity through PD-1 involvement in effector T cells. PD-L1 expression in the tumor correlates with decreased survival in esophageal, pancreatic and other types of cancer, highlighting this pathway as a target for immunotherapy. Triggering PD-1, expressed on monocytes and regulated for monocyte activation, by its ligand PD-L1 induces the production of IL-10 which inhibits the function of CD4 T cells.
In mice, gene expression is induced in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo apoptosis. Mice lacking this gene breed in the background of BALB/c develop dilated cardiomyopathy and die of congestive heart failure. These studies suggest that these gene products may also be important in T cell function and contribute to the prevention of autoimmune diseases.
PD1 overexpression of CD8 T cells is one indicator of T-cell fatigue (eg in chronic or cancerous infections).
Clinical interests
Cancer
PD-L1, ligand for PD1, is highly expressed in some cancers and hence the role of PD1 in cancer immune evasion is well known. Monoclonal antibodies targeting PD-1 that boost the immune system are being developed for cancer treatment. Many tumor cells express PD-L1, immunosuppressive PD-1 ligand; inhibition of interactions between PD-1 and PD-L1 can increase in-vitro cell responsiveness and mediate preclinical antitumor activity. These are known as block blocks of the immune system.
Combination therapy using anti-PD1 along with anti-CTLA4 therapy has emerged as an important tumor treatment in the field of inhibition of checkpoints.
The combination of PD1 and CTLA4 antibodies has proven to be more effective than antibodies alone in the treatment of various cancers. The effect of two antibodies does not seem excessive. The anti-CTLA4 treatment causes immune T-T cell-enhanced antigen-specific enhancement while anti-PD-1 appears to reactivate the ability of CD8 T cells to lyse cancer cells.
In clinical trials, combination therapy has been shown to be effective in reducing tumor size in patients unresponsive to single co-inhibitory blockade, despite increased toxicity rates due to anti-CTLA4 treatment. The combination of PD1 and CTLA4 induces up to ten times the number of CD8 T cells that actively infiltrate the tumor tissue. The authors hypothesize that higher rates of CD8 T T-cell infiltration are due to anti-CTLA-4 inhibiting the conversion of CD4 T-cells to regulatory T cells and further reducing regulatory suppression of T with anti-PD-1. This combination promotes a stronger inflammatory response to tumors that reduce the size of the cancer. Recently, the FDA has approved combination therapy with anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) in October 2015.
The molecular factors and receptors needed to make receptive tumors against anti-PD1 treatment remain unknown. PDL1 expression on the surface of cancer cells plays an important role. Positive PDL1 tumors are twice as likely to respond to treatment combinations. However patients with negative PDL1 tumors also had limited responses to anti-PD1, suggesting that PDL1 expression is not a critical determinant of therapeutic effectiveness.
The higher mutation burden on the tumor is correlated with a greater effect of anti-PD-1 treatment. In clinical trials, patients who benefit from anti-PD1 treatment have cancer, such as melanoma, bladder cancer, and gastric cancer, which have a median average number of mutations higher than patients who do not respond to therapy. However, the correlation between higher tumor burden and clinical effectiveness of PD-1 immune blockade is uncertain.
Anti-PD-1 therapeutics
A number of cancer immunotherapy agents targeting the PD-1 receptor have been developed.
One of the anti-PD-1, nivolumab, (Opdivo-Bristol Myers Squibb) antiviral drugs, produces a complete or partial response to non-small cell lung cancer, melanoma, and renal cell cancer, in a clinical trial of a total of 296 patients. Colon and pancreatic cancer have no response. Nivolumab (Opdivo, Bristol-Myers Squibb) was approved in Japan in July 2014 and by the US FDA in December 2014 to treat metastatic melanoma.
Pembrolizumab (Keytruda, MK-3475, Merck), which also targets the PD-1 receptor, has been approved by the FDA in September 2014 to treat metastatic melanoma. Pembrolizumab has been made accessible to patients with advanced melanoma in the UK through UK Early Access to Medicines Scheme (EAMS) in March 2015. It is used in clinical trials in the US for lung, lymphoma and mesothelioma cancer. It has measured success, with few side effects. It is up to the pharmaceutical manufacturers to apply to the FDA for approval for use in this disease. On October 2, 2015, Pembrolizumab is approved by the FDA for patients with advanced (non-small-cell) non-small-cell lung cancer (NSCLC) whose disease has developed after other treatments.
Other drugs in early stage development targeting the PD-1 receptor (examination inhibitors) are Pidilizumab (CT-011, Cure Tech) and BMS-936559 (Bristol Myers Squibb). Both Atezolizumab (MPDL3280A, Roche) and Avelumab (Merck KGaA, Darmstadt, Germany & Pfizer) target the same PD-L1 receptor.
Research on animals
HIV
Drugs targeting PD-1 in combination with other negative immune receptor posters, such as (TIGIT), can increase immune response and/or facilitate HIV eradication. T lymphocytes show an increased PD-1 expression in cases of chronic HIV infection. The high presence of PD-1 receptors is associated with the depletion of CD8 cytotoxic CD4 T cell populations and HIV-specific CD4s that are important in the fight against viruses. Immune blockade of PD-1 results in recovery of the inflammatory T-cell phenotype needed to combat disease progression.
Alzheimer's Disease
Blocking PD-1 leads to a decrease in cerebral amyloid? plaque and improve cognitive performance in mice. Immune blockade from PD-1 evokes IFN-? depending on the immune response that recruits the monocyte-derived macrophages to the brain which then are able to clear the amyloid? plaque from the tissues. Repeated administration with anti-PD-1 was found necessary to maintain the therapeutic effect of treatment. Amyloid fibrils are immunosuppressive and these findings have been confirmed separately by examining the effects of fibrils on neuroinflammatory disease. PD-1 neutralizes the effects of fibrils by increasing immune activity and triggering immune pathways that allow for brain repair.
References
Further reading
External links
- PDCD1 protein, man at National Library of Medicine US Subject of Medical Subject (MeSH)
This article combines text from the National Medical Library of the United States, which is in the public domain.
Source of the article : Wikipedia
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