Programmed cell death protein 1(PD-1) (CD279cluster of differentiation 279) is aprotein encoded in humans by thePDCD1gene.[5][6] PD-1 is acell surface receptor onT cells andB cells that has a role in regulating theimmune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressingT cell inflammatory activity. This preventsautoimmune diseases, but it can also prevent the immune system from killing cancer cells.[7]
PD-1 is animmune checkpoint and guards against autoimmunity through two mechanisms. First, it promotesapoptosis (programmed cell death) ofantigen-specific T-cells inlymph nodes. Second, it reduces apoptosis inregulatory T cells (anti-inflammatory, suppressive T cells).[8][9]
PD-1 inhibitors, a new class of drugs that block PD-1, activate the immune system to attack tumors and are used to treat certain types of cancer.[7][10]
In a screen for genes involved inapoptosis, Yasumasa Ishida,Tasuku Honjo and colleagues atKyoto 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]
In 2025, Yasumasa Ishida was part of a group that found that PD-1, together with its extracellular ligand "PD-L1" (the name given to the single gene precursor of both PD-L1 and PD-L2 genes in tetrapod species) and cytoplasmic tail binding phosphatases SHP-1 and SHP-2, and their interaction motifs, are well-conserved in evolution throughout jawed vertebrates (from the level of sharks) (Figure 2).[13] This corroborated partial findings by others.[14][15]
Figure 2. Evolution of PD-1 and its interacting molecules
PD-1 is atype I membrane protein of 288amino acids. PD-1 is a member of the extendedCD28/CTLA-4 family ofT cell regulators.[11] The protein's structure includes an extracellularIgV domain followed by atransmembrane region and an intracellular tail. The intracellular tail contains twophosphorylation sites located in animmunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates T-cell receptorTCR signals.[11][16] This is consistent with binding ofSHP-1 andSHP-2phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. In addition, PD-1 ligation up-regulatesE3 ubiquitin ligasesCBL-b and c-CBL that trigger T cell receptor down-modulation.[17][18] PD-1 is expressed on the surface of activated T cells,B cells, andmacrophages,[19] suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.
PD-1 has twoligands,PD-L1 andPD-L2, which are members of theB7 family.[20][21] PD-L1 protein is upregulated on macrophages anddendritic cells (DC) in response toLPS andGM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1mRNA can be detected in the heart, lung, thymus, spleen, and kidney.[20][22] PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, andB16 melanoma upon treatment withIFN-γ.[23][24] PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.[21]
Several lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. PD-1knockout mice have been shown to develop lupus-likeglomerulonephritis and dilatedcardiomyopathy on the C57BL/6 and BALB/c backgrounds, respectively.[25][26] In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion.[20] IFN-γ is a key pro-inflammatory cytokine that promotes T cell inflammatory activity. Reduced T cell proliferation was also correlated with attenuated IL-2 secretion and together, these data suggest that PD-1 negatively regulates T cell responses.[27]
Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg)CD4+ andCD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using anLCMV viral vector model of chronic infection, Rafi Ahmed's group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.[28]
Expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells.[23][24] 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][29] 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.[30]
In mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers ofthymocytes undergoapoptosis. Mice deficient for this gene bred on a BALB/c background developeddilated cardiomyopathy and died fromcongestive heart failure. These studies suggest that this gene product may also be important inT cell function and contribute to the prevention ofautoimmune diseases.[6]
Overexpression of PD1 on CD8+ T cells is one of the indicators ofT-cell exhaustion (e.g. in chronic infection or cancer).[7][31]
PD-L1, an immunosuppressive PD-1 ligand, is highly expressed in several cancers; the role of PD-1 in cancer immune evasion is well established.[33][34][7]Monoclonal antibodies targeting PD-1 that boost theimmune system are being developed for the treatment ofcancer.[7][35] Inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responsesin vitro and mediate preclinical antitumor activity. This is known asimmune checkpoint blockade.
PD-1 is expressed intrinsically in some tumor cells, such as melanoma, where it promotes tumor growth independently of the immune system. Inhibition of tumor cell-intrinsic PD-1 suppresses tumor growth, whereas overexpression or engagement by PD-L1 enhances tumorigenicity.[36]
Combination therapy using both anti-PD1 along with anti-CTLA4 therapeutics have emerged as important tumor treatments within the field ofcheckpoint inhibition. The effects of the two antibodies has been shown to be more effective than either antibody alone and does not appear to be redundant.[7][37][38][39] Anti-CTLA4 treatment leads to an enhanced antigen specific T cell dependent immune reaction while anti-PD-1 appears to reactivateCD8+ T cells ability to lyse cancer cells.[7][40][41]
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.[42] 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.[40] 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.[43]
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.[43][42] 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.[43]
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.[43]
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.[44] 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 metastaticmelanoma.
Pembrolizumab (Keytruda, MK-3475, Merck), which also targets PD-1 receptors, was approved by the FDA in Sept 2014 to treat metastaticmelanoma. 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.[45]
Toripalimab is a humanized IgG4 monoclonal antibody against PD-1 which was approved in China in 2018 and in the United States in 2023.[46][47][48]
Drugs targeting PD-1 in combination with other negative immune checkpoint receptors, such as (TIGIT), may augment immune responses and/or facilitateHIV eradication.[49][50] T lymphocytes exhibit elevated expression of PD-1 in cases of chronic HIV infection.[51] 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.[51]
Blocking of PD-1 leads to a reduction in cerebral amyloid-β plaques and improves cognitive performance in mice.[52] 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.[53][54][55] PD-1 counteracts the effects of the fibrils by boosting immune activity and triggering an immune pathway that allows for brain repair.[52]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (October 1994). "Structure and chromosomal localization of the human PD-1 gene (PDCD1)".Genomics.23 (3):704–6.doi:10.1006/geno.1994.1562.PMID7851902.
^Hu CB, Huang C, Wang J, Hong Y, Fan DD, Chen Y, et al. (September 2023). "PD-L1/BTLA Checkpoint Axis Exploited for Bacterial Immune Escape by Restraining CD8+ T Cell-Initiated Adaptive Immunity in Zebrafish".Journal of Immunology.211 (5):816–835.doi:10.4049/jimmunol.2300217.PMID37486225.
^Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. (May 1996). "Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes".International Immunology.8 (5):765–72.doi:10.1093/intimm/8.5.765.PMID8671665.
^abLatchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. (March 2001). "PD-L2 is a second ligand for PD-1 and inhibits T cell activation".Nature Immunology.2 (3):261–8.doi:10.1038/85330.PMID11224527.S2CID27659586.
^Gandini S, Massi D, Mandalà M (April 2016). "PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis".Critical Reviews in Oncology/Hematology.100:88–98.doi:10.1016/j.critrevonc.2016.02.001.PMID26895815.
^Weber J (October 2010). "Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical background: CTLA-4 and PD-1 blockade".Seminars in Oncology.37 (5):430–9.doi:10.1053/j.seminoncol.2010.09.005.PMID21074057.
^abBaruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, et al. (February 2016). "PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease".Nature Medicine.22 (2):135–7.doi:10.1038/nm.4022.PMID26779813.S2CID20699898.
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.doi:10.1006/excr.1997.3493.PMID9141617.
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.doi:10.1016/S0165-2478(02)00088-3.PMID12095712.
Prokunina L, Castillejo-López C, Oberg F, Gunnarsson I, Berg L, Magnusson V, et al. (December 2002). "A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans".Nature Genetics.32 (4):666–9.doi:10.1038/ng1020.PMID12402038.S2CID20496046.
Youngnak P, Kozono Y, Kozono H, Iwai H, Otsuki N, Jin H, et al. (August 2003). "Differential binding properties of B7-H1 and B7-DC to programmed death-1".Biochemical and Biophysical Research Communications.307 (3):672–7.Bibcode:2003BBRC..307..672Y.doi:10.1016/S0006-291X(03)01257-9.PMID12893276.
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.doi:10.1046/j.1399-0039.2003.00136.x.PMID14617032.
Prokunina L, Gunnarsson I, Sturfelt G, Truedsson L, Seligman VA, Olson JL, et al. (January 2004). "The systemic lupus erythematosus-associated PDCD1 polymorphism PD1.3A in lupus nephritis".Arthritis and Rheumatism.50 (1):327–8.doi:10.1002/art.11442.PMID14730631.
Lin SC, Yen JH, Tsai JJ, Tsai WC, Ou TT, Liu HW, et al. (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.doi:10.1002/art.20040.PMID15022318.
Prokunina L, Padyukov L, Bennet A, de Faire U, Wiman B, Prince J, et al. (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.doi:10.1002/art.20280.PMID15188352.
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.doi:10.1007/s00439-004-1172-0.PMID15322919.S2CID8562917.
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.doi:10.1191/0961203303lu1052oa.PMID15352422.S2CID33705026.
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.doi:10.1002/art.21058.PMID15934088.
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.doi:10.1016/j.cellimm.2005.07.007.PMID16171790.
Kobayashi M, Kawano S, Hatachi S, Kurimoto C, Okazaki T, Iwai Y, et al. (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.PMID16265694.
