PD-L1

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CD274
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CD274
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000120217

ENSMUSG00000016496

UniProt

Q9NZQ7

Q9EP73

RefSeq (mRNA)

NM_001314029
NM_001267706
NM_014143

NM_021893

RefSeq (protein)

NP_001254635
NP_001300958
NP_054862

NP_068693

Location (UCSC)Chr 9: 5.45 – 5.47 MbChr 19: 29.34 – 29.37 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 CD274 gene.[5]

Programmed death-ligand 1 (PD-L1) is a 40kDa type 1

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

Binding interactions

PD-L1 binds to its receptor,

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

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.[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

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

immunostain
.

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.
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

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

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.

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000120217 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000016496 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: CD274 CD274 molecule".
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  31. ^ Zaakouk, M.; Van Bockstal, M.; Galant, C.; Callagy, G.; Provenzano, E.; Hunt, R.; D’Arrigo, C.; Badr, N.M.; O’Sullivan, B.; Starczynski, J.; Tanchel, B.; Mir, Y.; Lewis, P.; Shaaban, A.M. Inter- and Intra-Observer Agreement of PD-L1 SP142 Scoring in Breast Carcinoma—A Large Multi-Institutional International Study. Cancers 2023, 15, 1511. https://doi.org/10.3390/cancers15051511
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External links
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