Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a
protein that in humans is encoded by the CD274gene.[5]
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
adaptive arm of
immune systems during particular events such as
pregnancy, tissue
allografts,
autoimmune disease and other disease states such as
hepatitis. Normally the adaptive immune system reacts to
antigens that are associated with immune system activation by exogenous or endogenous
danger signals. In turn, clonal expansion of
antigen-specific
CD8+ T cells and/or
CD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule
PD-1 transmits an inhibitory signal based on interaction with phosphatases (
SHP-1 or
SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM).[6] This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing
apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells) – further mediated by a lower regulation of the gene
Bcl-2.[citation needed]
History
PD-L1 also known as B7-H1 was characterized at the Mayo Clinic in 1999 as an immune regulatory molecule.[7] At that time, it was concluded that B7-H1 helps tumor cells evade anti-tumor immunity.[8] In 2003, B7-H1 was shown to be expressed on myeloid cells as checkpoint protein and was proposed as potential target in cancer immunotherapy in human clinic.[9]
Binding
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 770 nM. PD-L1 also has an appreciable affinity for the costimulatory molecule
CD80 (B7-1), but not
CD86 (B7-2).[10] CD80's affinity for PD-L1, 1.4 µM, is intermediate between its affinity for
CD28 and
CTLA-4 (4.0 µM and 400 nM, 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 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.[11]
Signaling
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.[12] PD-1 signaling attenuates
PKC-θactivation 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.[13]
Regulation
By interferons
Upon
IFN-γ stimulation, PD-L1 is expressed on T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, and vascular endothelial cells.[14] The PD-L1 gene promoter region has a response element to
IRF-1, the interferon regulatory factor.[15]Type I interferons can also upregulate PD-L1 on murine hepatocytes, monocytes, DCs, and tumor cells.[16]
On macrophages and monocytes
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.[17] 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.
It was also shown that PD-L1 is constituvely expressed on mouse Ly6Clo nonclassical
monocytes in steady state.[18]
Role of microRNAs
Resting human
cholangiocytes express PD-L1 mRNA, but not the protein, due to translational suppression by
microRNA miR-513.[19] 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 the Epstein-Barr viral (EBV) latent membrane protein-1 (LMP1) is a known potent inducer of PD-L1, the EBV miRNA miR-BamH1 fragment H rightward
open reading frame 1 (BHRF1) 2-5p has been shown to regulate LMP1 induced PD-L1 expression.[20]
Epigenetic regulation
PD-L1 promoter DNA methylation may predict survival in some cancers after surgery.[21]
Clinical significance
Cancer
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.[22] 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 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.[23]
Many
PD-L1 inhibitors are in development as immuno-oncology therapies and are showing good results in clinical trials.[24] Clinically available examples include
durvalumab,
atezolizumab and
avelumab.[25]
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.[26]CAR-T[27] and
NK cells[28] targeting PD-L1 are being evaluated for treating cancer. pSTAT-1 and PDL-1 expressions also strongly correlate in prostate cancer.[29]
Upregulation of PD-L1 on immune cells (especially
myeloid cells) can also lead to formation of an immunosuppressive environment in a highly localized manner that also allow the cancer cells to proliferate.[30]
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.[31]
Listeria monocytogenes
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).[32] This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection.
Autoimmunity
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 the
gastrin expressing
G-cells from the immune system during
Helicobacter pylori-provoked inflammation.[33] 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).[34]
In humans, PD-L1 was found to have altered expression in pediatric patients with
systemic lupus erythematosus (SLE). 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.[35] This may be one mechanism whereby peripheral 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.
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^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.
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^Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. (September 2004). "PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta". FEBS Letters. 574 (1–3): 37–41.
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^Flies DB, Chen L (April 2007). "The new B7s: playing a pivotal role in tumor immunity". Journal of Immunotherapy. 30 (3): 251–260.
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^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.
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