Programmed cell death protein 1
PDCD1 | |||
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Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process |
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Sources:Amigo / QuickGO |
Ensembl | |||||||||
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UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 2: 241.85 – 241.86 Mb | Chr 1: 93.97 – 93.98 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Programmed cell death protein 1 (PD-1), (CD279
PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. First, it promotes apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes. Second, it reduces apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).[8][9]
PD-1 is a cell surface receptor that belongs to the
Discovery
In a screen for genes involved in apoptosis, Yasumasa Ishida, Tasuku Honjo and colleagues at Kyoto University in 1992 discovered and named PD-1.[11][12] In 1999, the same group demonstrated that mice where PD-1 was knocked down were prone to autoimmune disease and hence concluded that PD-1 was a negative regulator of immune responses.[12]
Structure
PD-1 is a type I
Ligands
PD-1 has two
Function
Several lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. PD-1
Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg)
Expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells.[19][20] Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighting this pathway as a target for immunotherapy.[7][25] Triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.[26]
In mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers of
Overexpression of PD1 on CD8+ T cells is one of the indicators of
Clinical significance
Cancer
PD-L1, the ligand for PD1, is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established.
Combination therapy using both anti-PD1 along with anti-
A combination of PD1 and CTLA4 antibodies has been shown to be more effective than either antibody alone in the treatment of a variety of cancers. The effects of the two antibodies do not appear to be redundant.[7][32][33][34] Anti-CTLA4 treatment leads to an enhanced antigen specific T cell dependent immune reaction while anti-PD-1 appears to reactivate CD8+ T cells ability to lyse cancer cells.[7][35][36]
In clinical trials, combination therapy has been shown to be effective in reducing tumor size in patients that are unresponsive to single co-inhibitory blockade, despite increasing levels of toxicity due to anti-CTLA4 treatment.[37] A combination of PD1 and CTLA4 induced up to a ten-fold higher number of CD8+ T cells that are actively infiltrating the tumor tissue.[35] The authors hypothesized that the higher levels of CD8+ T cell infiltration was due to anti-CTLA-4 inhibited the conversion of CD4 T cells to T regulator cells and further reduced T regulatory suppression with anti-PD-1. This combination promoted a more robust inflammatory response to the tumor that reduced the size of the cancer. Most recently, the FDA has approved a combination therapy with both anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) in October 2015.[38]
The molecular factors and receptors necessary making a tumor receptive to anti-PD1 treatment remains unknown. PD-L1 expression on the surface on cancer cells plays a significant role. PD-L1 positive tumors were twice as likely to respond to combination treatment.[38][37] However patients with PD-L1 negative tumors also have limited response to anti-PD1, demonstrating that PD-L1 expression is not an absolute determinant of the effectiveness of therapy.[38]
Higher mutational burden in the tumor is correlated with a greater effect of the anti-PD-1 treatment. In clinical trials, patients who benefited from anti-PD1 treatment had cancers, such as melanoma, bladder cancer, and gastric cancer, that had a median higher average number of mutations than the patients who did not respond to the therapy. However, the correlation between higher tumor burden and the clinical effectiveness of PD-1 immune blockade is still uncertain.[38]
The 2018
Anti-PD-1 therapeutics
A number of cancer immunotherapy agents that target the PD-1 receptor have been developed.
One such anti-PD-1 antibody drug, nivolumab, (Opdivo - Bristol Myers Squibb), produced complete or partial responses in non-small-cell lung cancer, melanoma, and renal-cell cancer, in a clinical trial with a total of 296 patients.[39] Colon and pancreatic cancer did not have a 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 PD-1 receptors, was approved by the FDA in Sept 2014 to treat metastatic melanoma. Pembrolizumab has been made accessible to advanced melanoma patients in the UK via UK Early Access to Medicines Scheme (EAMS) in March 2015. It is being used in clinical trials in the US for lung cancer, lymphoma, and mesothelioma. It has had measured success, with little side effects.[7] It is up to the manufacturer of the drug to submit application to the FDA for approval for use in these diseases. On October 2, 2015, Pembrolizumab was approved by FDA for advanced (metastatic) non-small cell lung cancer (NSCLC) patients whose disease has progressed after other treatments.[40]
Toripalimab is a humanized IgG4 monoclonal antibody against PD-1 which was approved in China in 2018 and in the United States in 2023.[41][42][43]
Drugs in early stage development targeting PD-1 receptors (
Animal studies
HIV
Drugs targeting PD-1 in combination with other negative immune checkpoint receptors, such as (TIGIT), may augment immune responses and/or facilitate HIV eradication.[44][45] T lymphocytes exhibit elevated expression of PD-1 in cases of chronic HIV infection.[46] Heightened presence of the PD-1 receptors corresponds to exhaustion of the HIV specific CD8+ cytotoxic and CD4+ helper T cell populations that are vital in combating the virus. Immune blockade of PD-1 resulted in restoration of T cell inflammatory phenotype necessary to combat the progression of disease.[46]
Alzheimer's disease
Blocking of PD-1 leads to a reduction in cerebral amyloid-β plaques and improves cognitive performance in mice.[47] Immune blockade of PD-1 evoked an IFN-γ dependent immune response that recruited monocyte-derived macrophages to the brain that were then capable of clearing the amyloid-β plaques from the tissue. Repeated administrations with anti-PD-1 were found to be necessary to maintain the therapeutic effects of the treatment. Amyloid fibrils are immunosuppressive and this finding has been separately confirmed by examining the effects of the fibrils in neuroinflammatory diseases.[48][49][50] PD-1 counteracts the effects of the fibrils by boosting immune activity and triggering an immune pathway that allows for brain repair.[47]
References
- ^ a b c ENSG00000276977 GRCh38: Ensembl release 89: ENSG00000188389, ENSG00000276977 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026285 - Ensembl, May 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ a b c "Entrez Gene: PDCD1 programmed cell death 1".
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- Andrew Pollack (June 1, 2012). "Drug Helps Defense System Fight Cancer". The New York Times.
- ^ "FDA approves Keytruda for advanced non-small cell lung cancer". U.S. Food and Drug Administration (FDA) Press Release. 2 October 2015.
- ^ "Toripalimab - Shanghai Junshi Biosciences - AdisInsight". adisinsight.springer.com. Retrieved 2019-08-25.
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- ^ "FDA approves toripalimab-tpzi for nasopharyngeal carcinoma". US Food and Drug Administration. October 27, 2023.
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Further reading
- Vibhakar R, Juan G, Traganos F, Darzynkiewicz Z, Finger LR (April 1997). "Activation-induced expression of human programmed death-1 gene in T-lymphocytes". Experimental Cell Research. 232 (1): 25–8. PMID 9141617.
- Finger LR, Pu J, Wasserman R, Vibhakar R, Louie E, Hardy RR, Burrows PD, Billips LG (September 1997). "The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors". Gene. 197 (1–2): 177–87. PMID 9332365.
- Iwai Y, Okazaki T, Nishimura H, Kawasaki A, Yagita H, Honjo T (October 2002). "Microanatomical localization of PD-1 in human tonsils". Immunology Letters. 83 (3): 215–20. PMID 12095712.
- Prokunina L, Castillejo-López C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdóttir H, Gröndal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jönssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcón-Segovia D, Steinsson K, Alarcón-Riquelme ME (December 2002). "A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans". Nature Genetics. 32 (4): 666–9. S2CID 20496046.
- Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, Lowe D, Khan N, Veldman G, Jacobs KA, Valge-Archer VE, Collins M, Carreno BM (January 2003). "Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses". Journal of Immunology. 170 (2): 711–8. PMID 12517932.
- Wang S, Bajorath J, Flies DB, Dong H, Honjo T, Chen L (May 2003). "Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction". The Journal of Experimental Medicine. 197 (9): 1083–91. PMID 12719480.
- Youngnak P, Kozono Y, Kozono H, Iwai H, Otsuki N, Jin H, Omura K, Yagita H, Pardoll DM, Chen L, Azuma M (August 2003). "Differential binding properties of B7-H1 and B7-DC to programmed death-1". Biochemical and Biophysical Research Communications. 307 (3): 672–7. PMID 12893276.
- Nielsen C, Hansen D, Husby S, Jacobsen BB, Lillevang ST (December 2003). "Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes". Tissue Antigens. 62 (6): 492–7. PMID 14617032.
- Prokunina L, Gunnarsson I, Sturfelt G, Truedsson L, Seligman VA, Olson JL, Seldin MF, Criswell LA, Alarcón-Riquelme ME (January 2004). "The systemic lupus erythematosus-associated PDCD1 polymorphism PD1.3A in lupus nephritis". Arthritis and Rheumatism. 50 (1): 327–8. PMID 14730631.
- Lin SC, Yen JH, Tsai JJ, Tsai WC, Ou TT, Liu HW, Chen CJ (March 2004). "Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus". Arthritis and Rheumatism. 50 (3): 770–5. PMID 15022318.
- Prokunina L, Padyukov L, Bennet A, de Faire U, Wiman B, Prince J, Alfredsson L, Klareskog L, Alarcón-Riquelme M (June 2004). "Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope". Arthritis and Rheumatism. 50 (6): 1770–3. PMID 15188352.
- Sanghera DK, Manzi S, Bontempo F, Nestlerode C, Kamboh MI (October 2004). "Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies". Human Genetics. 115 (5): 393–8. S2CID 8562917.
- Nielsen C, Laustrup H, Voss A, Junker P, Husby S, Lillevang ST (2005). "A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients". Lupus. 13 (7): 510–6. S2CID 33705026.
- Johansson M, Arlestig L, Möller B, Rantapää-Dahlqvist S (June 2005). "Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus". Arthritis and Rheumatism. 52 (6): 1665–9. PMID 15934088.
- Nielsen C, Ohm-Laursen L, Barington T, Husby S, Lillevang ST (June 2005). "Alternative splice variants of the human PD-1 gene". Cellular Immunology. 235 (2): 109–16. PMID 16171790.
- Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (November 2005). "CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms". Molecular and Cellular Biology. 25 (21): 9543–53. PMID 16227604.
- Kobayashi M, Kawano S, Hatachi S, Kurimoto C, Okazaki T, Iwai Y, Honjo T, Tanaka Y, Minato N, Komori T, Maeda S, Kumagai S (November 2005). "Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sjögren's syndrome". The Journal of Rheumatology. 32 (11): 2156–63. PMID 16265694.
External links
- PDCD1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: Q15116 (Programmed cell death protein 1) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.