|, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1, PDL1, CD274 molecule, Programmed cell death 1 ligand 1|
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Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the immune system reacts to foreign antigens where there is some accumulation in the lymph nodes or spleen which triggers a proliferation of antigen-specific CD8+ T cell. The binding of PD-L1 to PD-1 or B7.1 transmits an inhibitory signal which reduces the proliferation of these CD8+ T cells at the lymph nodes and supplementary to that PD-1 is also able to control the accumulation of foreign antigen specific T cells in the lymph nodes through apoptosis which is further mediated by a lower regulation of the gene Bcl-2.
PD-L1 binds to its receptor, PD-1, found on activated T cells, B cells, and myeloid cells, to modulate activation or inhibition. The affinity between PD-L1 and PD-1, as defined by the dissociation constant Kd, is 770nM. Interestingly, PD-L1 also has an appreciable affinity for the costimulatory molecule CD80 (B7-1), but not CD86 (B7-2). CD80's affinity for PD-L1, 1.4µM, is intermediate between its affinities for CD28 and CTLA-4 (4.0µM and 400nM, respectively). The related molecule PD-L2 has no such affinity for CD80 or CD86, but shares PD-1 as a receptor (with a stronger Kd of 140nM). Said et al. showed that PD-1, up-regulated on activated CD4 T-cells, can bind to PD-L1 expressed on monocytes and induces IL-10 production by the latter.
Engagement of PD-L1 with its receptor PD-1 on T cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. The mechanism involves inhibition of ZAP70 phosphorylation and its association with CD3ζ. PD-1 signaling attenuates PKC-θ activation loop phosphorylation (resulting from TCR signaling), necessary for the activation of transcription factors NF-κB and AP-1, and for production of IL-2. PD-L1 binding to PD-1 also contributes to ligand-induced TCR down-modulation during antigen presentation to naive T cells, by inducing the up-regulation of the E3 ubiquitin ligase CBL-b.
Upon IFN-γ stimulation, PD-L1 is expressed on T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, and vascular endothelial cells. The PD-L1 gene promoter region has a response element to IRF-1, the interferon regulatory factor. Type I interferons can also upregulate PD-L1 on murine hepatocytes, monocytes, DCs, and tumor cells.
PD-L1 is notably expressed on macrophages. In the mouse, it has been shown that classically activated macrophages (induced by type I helper T cells or a combination of LPS and interferon-gamma) greatly upregulate PD-L1. Alternatively, macrophages activated by IL-4 (alternative macrophages), slightly upregulate PD-L1, while greatly upregulating PD-L2. It has been shown by STAT1-deficient knock-out mice that STAT1 is mostly responsible for upregulation of PD-L1 on macrophages by LPS or interferon-gamma, but is not at all responsible for its constitutive expression before activation in these mice.
Role of MicroRNAs
Resting human cholangiocytes express PD-L1 mRNA, but not the protein, due to translational suppression by microRNA miR-513. Upon treatment with interferon-gamma, miR-513 was down-regulated, thereby lifting suppression of PD-L1 protein. In this way, interferon-gamma can induce PD-L1 protein expression by inhibiting gene-mediated suppression of mRNA translation.
It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of 196 tumor specimens from patients with renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death. Ovarian cancer patients with higher expression of PD-L1 had a significantly poorer prognosis than those with lower expression. PD-L1 expression correlated inversely with intraepithelial CD8+ T-lymphocyte count, suggesting that PD-L1 on tumor cells may suppress antitumor CD8+ T cells. Many PD-L1 inhibitors are in development as immuno-oncology therapies and are showing good results in clinical trials. These include an engineered Affimer biotherapeutic from Avacta Life Sciences and anti-PD-L1 antibodies from Medimmune, Genentech and Merck and Pfizer.
In a mouse model of intracellular infection, L. monocytogenes induced PD-L1 protein expression in T cells, NK cells, and macrophages. PD-L1 blockade (using blocking antibodies) resulted in increased mortality for infected mice. Blockade reduced TNFα and nitric oxide production by macrophages, reduced granzyme B production by NK cells, and decreased proliferation of L. monocytogenes antigen-specific CD8 T cells (but not CD4 T cells). This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection.
The PD-1/PD-L1 interaction is implicated in autoimmunity from several lines of evidence. NOD mice, an animal model for autoimmunity that exhibit a susceptibility to spontaneous development of type I diabetes and other autoimmune diseases, have been shown to develop precipitated onset of diabetes from blockade of PD-1 or PD-L1 (but not PD-L2).
In humans, PD-L1 was found to have altered expression in pediatric patients with Systemic lupus erythematosus. Studying isolated PBMC from healthy children, immature myeloid dendritic cells and monocytes expressed little PD-L1 at initial isolation, but spontaneously up-regulated PD-L1 by 24 hours. In contrast, both mDC and monocytes from patients with active SLE failed to upregulate PD-L1 over a 5 day time course, expressing this protein only during disease remissions. This may be one mechanism whereby peripheral tolerance is lost in SLE.
- "Entrez Gene: CD274 CD274 molecule".
- Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL (July 2004). "SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation". Journal of Immunology 173 (2): 945–54. doi:10.4049/jimmunol.173.2.945. PMID 15240681.
- Butte MJ, Peña-Cruz V, Kim MJ, Freeman GJ, Sharpe AH (August 2008). "Interaction of human PD-L1 and B7-1". Mol Immunol. 45 (13): 3567–72. doi:10.1016/j.molimm.2008.05.014. PMC 3764616. PMID 18585785.
- Said, E. A.; Dupuy, F. P.; Trautmann, L; Zhang, Y; Shi, Y; El-Far, M; Hill, B. J.; Noto, A; Ancuta, P; Peretz, Y; Fonseca, S. G.; Van Grevenynghe, J; Boulassel, M. R.; Bruneau, J; Shoukry, N. H.; Routy, J. P.; Douek, D. C.; Haddad, E. K.; Sekaly, R. P. (2010). "Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection". Nature Medicine 16 (4): 452–9. doi:10.1038/nm.2106. PMC 4229134. PMID 20208540.
- Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D (September 2004). "PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta.". FEBS Lett. 574 (1-3): 37–41. doi:10.1016/j.febslet.2004.07.083. PMID 15358536.
- Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D (August 2011). "PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells". EMBO Molecular Medicine 3 (10): 581–92. doi:10.1002/emmm.201100165. PMID 21739608.
- Flies DB, Chen L (April 2007). "The new B7s: playing a pivotal role in tumor immunity". J Immunother. 30 (3): 251–60. doi:10.1097/CJI.0b013e31802e085a. PMID 17414316.
- Lee SJ, Jang BC, Lee SW, Yang YI, Suh SI, Park YM, Oh S, Shin JG, Yao S, Chen L, Choi IH (February 2006). "Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274)". FEBS Lett. 580 (3): 755–62. doi:10.1016/j.febslet.2005.12.093. PMID 16413538.
- Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H (November 2002). "Expression of programmed death 1 ligands by murine T cells and APC.". Journal of Immunology 169 (10): 5538–45. doi:10.4049/jimmunol.169.10.5538. PMID 12421930.
- Loke P, Allison JP (April 2003). "PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5336–41. doi:10.1073/pnas.0931259100. PMC 154346. PMID 12697896.
- Gong AY, Zhou R, Hu G, Li X, Splinter PL, O'Hara SP, LaRusso NF, Soukup GA, Dong H, Chen XM (February 2009). "MicroRNA-513 regulates B7-H1 translation and is involved in IFN-gamma-induced B7-H1 expression in cholangiocytes". Journal of Immunology 182 (3): 1325–33. doi:10.4049/jimmunol.182.3.1325. PMC 2652126. PMID 19155478.
- Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, Zincke H, Blute ML, Strome SE, Leibovich BC, Kwon ED (December 2004). "Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target". Proc Natl Acad Sci USA 101 (49): 17174–9. doi:10.1073/pnas.0406351101. PMC 534606. PMID 15569934.
- Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S (February 2007). "Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer". Proc Natl Acad Sci USA 104 (9): 3360–5. doi:10.1073/pnas.0611533104. PMC 1805580. PMID 17360651.
- Velcheti V (Jan 2014). "Programmed death ligand-1 expression in non-small cell lung cancer". Lab Invest. 94 (1): 107–115. doi:10.1038/labinvest.2013.130. PMID 24217091.
- Avacta Life Sciences. "Affimer biotherapeutics target cancer's off-switch with PD-L1 inhibitor".
- Cure today. "Durvalumab continues to progress in treatment of advanced bladder cancer.".
- Roche. "FDA grants priority review for Roche's cancer immunotherapy atezolizumab in specific type of lung cancer".
- Merck Group. "Immuno-oncology Avelumab".
- Seo SK, Jeong HY, Park SG, Lee SW, Choi IW, Chen L, Choi I (January 2008). "Blockade of endogenous B7-H1 suppresses antibacterial protection after primary Listeria monocytogenes infection". Immunology 123 (1): 90–9. doi:10.1111/j.1365-2567.2007.02708.x. PMC 2433284. PMID 17971153.
- Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H Jr, Sayegh MH (July 2003). "The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice". J Exp Med. 198 (1): 63–9. doi:10.1084/jem.20022125. PMC 2196083. PMID 12847137.
- Mozaffarian N, Wiedeman AE, Stevens AM (July 2008). "Active systemic lupus erythematosus is associated with failure of antigen-presenting cells to express programmed death ligand-1". Rheumatology (Oxford) 47 (9): 1335–41. doi:10.1093/rheumatology/ken256. PMC 2722808. PMID 18650228.