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PD-1, also referred to as CD279, was first discovered in interleukin-3 (IL-3)-deprived LyD9 (murine hematopoietic progenitor) and 2B4-11 (murine T-cell hybridoma) cell lines in 1992 [Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. 1992]. PD-1 is 15% similar to the amino acid sequence of CD28, 20% similar to CTLA4, and 13% similar to induced T-cell co-stimulator [Carreno BM, Collins M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses, 2002]. PD-1 is a 55-kDa transmembrane protein containing 288 amino acids with an extracellular N-terminal domain (IgV-Like), a membrane-permeating domain and a cytoplasmic tail located at the N and C ends, respectively, with two tyrosine base
As stated, typically triggered by an NEMO-dependent activation of IKK, phosphorylation of IκB proteins followed by ubiquitination and degradation by proteasomes releases the NF-κB p65:p50 dimers from the inhibitory complex.( Collins P, Mitxitorena I, Carmody R. The ubiquitination of NF-κB subunits in the control of transcription. 2016)
PD-1 is an inhibitor of both adaptive and innate immune responses, and is expressed on activated T, natural killer (NK) and B lymphocytes, macrophages, dendritic cells (DCs) and monocytes. Of note, PD-1 is highly expressed on tumor-specific T cells [Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. 2009]. Transcription factors such as nuclear factor of activated T cells (NFAT), NOTCH, Forkhead box protein (FOX) O1 and interferon (IFN) regulatory factor 9 (IRF9) may trigger the transcription of PD-1 [Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection. 2014]. The conserved upstream regulatory regions B and C (CR-B and COR-C) are important for the expression of the PD-1 gene. There is a binding site in the CR-C region that is connected to NFATc1 (NFAT2) in TCD4 and TCD8 units. Instead, c-FOS connects to sites in the CR-B region and enhances PD-1 expression when it stimulates T-cell receptors upon Ag detection in naive T cells. NFATc is activated and binds to the promoter region of the pdcd1 gene [ Li C, Li W, Xiao J, Jiao S, Teng F, Xue S, Zhang C, Sheng C, Leng Q, Rudd CE, Wei B, Wang H. ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy. 2015]. In addition, IFN-α combined with IRF9 may result in PD-1 expression via binding to the promoter of the pdcd1 gene in exhausted T cells. During chronic infections.
PD-1 is expressed in exhausted TCD8 cells due to its demethylated promoter, and the FOXO1 transcription factor binds to the PD-1 promoter to increase its expression [Youngblood B, Oestreich KJ, Ha SJ, Duraiswamy J, Akondy RS, West EE, Wei Z, Lu P, Austin JW, Riley JL, Boss JM, Ahmed R. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8+ T cells. 2011].
Cancer cell leakage increases the expression of the c-FOS subunit of AP1, thereby increasing the expression of PD-1 [Xiao G, Deng A, Liu H, Ge G, Liu X. Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1. 2012].
PD-1 plays two opposing roles, as it can be both beneficial and harmful. As regards its beneficial effects, it plays a key role in reducing the regulation of ineffective or harmful immune responses and maintaining immune tolerance. However, PD-1 causes the dilation of malignant cells by interfering with the protective immune response [Salmaninejad A, Khoramshahi V, Azani A, Soltaninejad E, Aslani S, Zamani MR, Zal M, Nesaei A, Hosseini SM. PD-1 and cancer: molecular mechanisms and polymorphisms. 2018].
PD-1 ligand (PD-L1; also referred to as CD279 and B7-H1), belongs to the B7 series and is a 33-kDa type 1 transmembrane glycoprotein that contains 290 amino acids with Ig- and IgC domains in its extracellular region [Sanmamed MF, Chen L. Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. 2014].
PD-L1 is usually expressed by macrophages, some activated T cells and B cells, DCs and some epithelial cells, particularly under inflammatory conditions [Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. 2007]. In addition, PD-L1 is expressed by tumor cells as an “adaptive immune mechanism” to escape anti-tumor responses. PD-L1 is associated with an immune environment rich in CD8 T cells, production of Th1 cytokines and chemical factors, as well as interferons and specific gene expression characteristics [ Ji M, Liu Y, Li Q, Li XD, Zhao WQ, Zhang H, Zhang X, Jiang JT, Wu CP. PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation. 2015]. It has been demonstrated that IFN-γ causes PD-L1 upregulation in ovarian cancer cells, which is responsible for disease progression, whereas IFN-γ receptor 1 inhibition can reduce PD-L1 expression in acute myeloid leukemia mouse models through the MEK/extracellular signal-regulated kinase (ERK) and MYD88/TRAF6 pathways [Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai M. IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. 2015]. IFN-γ induces protein kinase D isoform 2 (PKD2), which is important for the regulation of PD-L1. Inhibition of PKD2 activity inhibits the expression of PD-L1 and promotes a strong antitumor immune response. NK cells secrete IFN-γ through the Janus kinase (JAK)1, JAK2 and signal transducer and activator of transcription (STAT)1 pathways, increasing the expression of PD-L1 on the surface of the tumor cells. Studies on melanoma cells have shown that IFN-γ secreted by T cells through the JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 pathway may regulate the expression of PD-L1. T and NK cells appear to secrete IFN-γ, which induces PD-L1 expression on the surface of the target cells, including tumor cells [ Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, Zaretsky JM, Sun L, Hugo W, Wang X, Parisi G, Saus CP, Torrejon DY, Graeber TG, Comin-Anduix B, Hu-Lieskovan S, Damoiseaux R, Lo RS, Ribas A. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. 2017].
PD-L1 acts as a pro-tumorigenic factor in cancer cells via binding to its receptors and activating proliferative and survival signaling pathways [Dong P, Xiong Y, Yue J, Hanley SJB, Watari H. Tumor-intrinsic PD-L1 signaling in cancer initiation, development and treatment: beyond immune evasion, 2018]. This finding further indicated that PD-L1 is implicated in subsequent tumor progression. In addition, PD-L1 has been shown to exert non-immune proliferative effects on a variety of tumor cell types. For example, PD-L1 induced epithelial-to-mesenchymal transition (EMT) and stem cell-like phenotypes in renal cancer cells, indicating that the presence of the intrinsic pathway of PD-L1 promotes kidney cancer progression [ Nunes-Xavier CE, Angulo JC, Pulido R, López JI. A critical insight into the clinical translation of PD-1/PD-L1 blockade therapy in clear cell renalcell carcinoma. 2019].