Programmed death-ligand 1 (PD-L1) also known ascluster of differentiation 274 (CD274) orB7 homolog 1 (B7-H1) is aprotein that in humans is encoded by theCD274gene.[5]
Programmed death-ligand 1 (PD-L1) is a 40kDa type 1transmembrane protein that has been speculated to play a major role in suppressing theadaptive arm ofimmune systems during particular events such aspregnancy, tissueallografts,autoimmune disease and other disease states such ashepatitis. Normally the adaptive immune system reacts toantigens that are associated with immune system activation by exogenous or endogenousdanger signals. In turn, clonal expansion ofantigen-specificCD8+ T cells and/orCD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint moleculePD-1 transmits an inhibitory signal based on interaction withphosphatases (SHP-1 orSHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM).[6] This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducingapoptosis inregulatory T cells (anti-inflammatory, suppressive T cells) – further mediated by a lower regulation of the geneBcl-2.[citation needed]. PD-L1 is expressed on bothhematopoietic and nonhematopoietic cells in tissues. However, the exact roles of PD-L1 on hematopoietic versus nonhematopoietic cells in modulating immune responses are unclear.[7]
PD-L1 also known as B7-H1 was characterized at the Mayo Clinic in 1999 as an immune regulatory molecule.[8] At that time, it was concluded that B7-H1 helps tumor cells evade anti-tumor immunity.[9] In 2003, B7-H1 was shown to be expressed on myeloid cells as checkpoint protein and was proposed as potential target incancer immunotherapy in human clinic.[10]
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 thedissociation constant Kd, is 770 nM. PD-L1 also has an appreciable affinity for thecostimulatory moleculeCD80 (B7-1), but notCD86 (B7-2).[11] CD80's affinity for PD-L1, 1.4 μM, is intermediate between its affinity forCD28 andCTLA-4 (4.0 μM and 400 nM, respectively). The related moleculePD-L2 has no such affinity for CD80 or CD86, but shares PD-1 as a receptor (with a stronger Kd of 140 nM). 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.[12]
Engagement of PD-L1 with its receptorPD-1 on T cells delivers a signal that inhibitsTCR-mediated activation ofIL-2 production and T cell proliferation. The mechanism involves inhibition ofZAP70 phosphorylation and its association withCD3ζ.[13] PD-1 signaling attenuatesPKC-θactivation loop phosphorylation (resulting from TCR signaling), necessary for the activation of transcription factorsNF-κB andAP-1, and for production of IL-2. PD-L1 binding to PD-1 also contributes to ligand-induced TCR down-modulation during antigen presentation tonaive T cells, by inducing the up-regulation of theE3 ubiquitin ligaseCBL-b.[14]
PD-L1 is notably expressed onmacrophages. In the mouse, it has been shown that classically activated macrophages (induced by type Ihelper T cells or a combination ofLPS andinterferon-gamma) greatly upregulate PD-L1.[18] Alternatively, macrophages activated byIL-4 (alternative macrophages),slightly upregulate PD-L1, while greatly upregulating PD-L2. It has been shown bySTAT1-deficientknock-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 itsconstitutive expression before activation in these mice.It was also shown that PD-L1 is constituvely expressed on mouse Ly6Clo nonclassicalmonocytes in steady state.[19]
Resting humancholangiocytes express PD-L1mRNA, but not the protein, due to translational suppression bymicroRNA miR-513.[20] 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. Whereas theEpstein-Barr viral (EBV)latent membrane protein-1 (LMP1) is a known potent inducer of PD-L1, the EBV miRNA miR-BamH1 fragment H rightwardopen reading frame 1 (BHRF1) 2-5p has been shown to regulate LMP1 induced PD-L1 expression.[21]
PD-L1 is shown to be highly expressed in a variety of malignancies, particularly lung cancer. In order to anticipate the effectiveness of gene therapy or systemic immunotherapy in blocking the PD-1 and PD-L1 checkpoints, PD-L1 might be employed as a prognostic marker and a target for anti-cancer immunity.[23] i.e. upregulation of PD-L1 may allow cancers to evade the host immune system. For example, an analysis of 196 tumor specimens from patients withrenal 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.[24] In a model ofA20 leukemia cells injected into F1 mice, NK cells killed target tumor cells with similar efficiency regardless of PD-L1 expression, whereas PD-L1 expression on A20 tumor cells conferred significant tumor protection against rejection by CD8 T cells confirming the role of the co-inhibitory receptor PD-1 in the modulation of their cytotoxic activity.[25]
ManyPD-L1 inhibitors are in development as immuno-oncology therapies and are showing good results in clinical trials.[26] Clinically available examples includedurvalumab,atezolizumab andavelumab.[27]In normal tissue, feedback between transcription factors like STAT3 and NF-κB restricts the immune response to protect host tissue and limit inflammation. In cancer, loss of feedback restriction between transcription factors can lead to increased local PD-L1 expression, which could limit the effectiveness of systemic treatment with agents targeting PD-L1.[28]CAR-T[29] andNK cells[30] targeting PD-L1 are being evaluated for treating cancer. pSTAT-1 and PDL-1 expressions also strongly correlate in prostate cancer.[31]
Upregulation of PD-L1 on immune cells (especiallymyeloid cells) can also lead to formation of an immunosuppressive environment in a highly localized manner that also allow the cancer cells to proliferate.[32]
PD-L1 analysis in TNBC is essential for selecting patients eligible for immunotherapy. Inter-observer and intra-observer agreement among the pathologists were found to be substantial. Cases around the 1% cut-off value are specifically challenging.[33]
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 reducedTNFα and nitric oxide production by macrophages, reducedgranzyme B production by NK cells, and decreased proliferation ofL. monocytogenes antigen-specific CD8 T cells (but not CD4 T cells).[34] This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection.
PD-1/PD-L1 interaction is thought to play a role in preventing destructive autoimmunity, especially during inflammatory conditions. The best example is in the stomach, where PD-1 expression protects thegastrin expressingG-cells from the immune system duringHelicobacter pylori-provoked inflammation.[35] But also a variety of pre-clinical studies support the notion that the PD-1/PD-L1 interaction is implicated in autoimmunity.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).[36]
In humans, PD-L1 was found to have altered expression in pediatric patients withsystemic lupus erythematosus (SLE). Studying isolatedPBMC from healthy children, immaturemyeloid dendritic cells andmonocytes 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.[37] This may be one mechanism wherebyperipheral tolerance is lost in SLE.
^Dong H, Zhu G, Tamada K, Chen L (December 1999). "B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion".Nature Medicine.5 (12):1365–1369.doi:10.1038/70932.PMID10581077.S2CID21397460.
^Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. (August 2002). "Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion".Nature Medicine.8 (8):793–800.doi:10.1038/nm730.PMID12091876.S2CID27694471.
^Kazan O, Kir G, Culpan M, Cecikoglu GE, Atis G, Yildirim A (July 2022). "The association between PI3K, JAK/STAT pathways with the PDL-1 expression in prostate cancer".Andrologia.54 (e14541): e14541.doi:10.1111/and.14541.PMID35880672.S2CID251068796.
