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Review
. 2021 Jun 17;13(12):3034.
doi: 10.3390/cancers13123034.

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Christian Bailly  1 , Xavier Thuru  2 , Bruno Quesnel  2
Affiliations
Review

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Christian Bailly et al. Cancers (Basel). .

Abstract

Upon T-cell receptor stimulation, the Programmed cell Death-1 receptor (PD-1) expressed on T-cells can interact with its ligand PD-L1 expressed at the surface of cancer cells or antigen-presenting cells. Monoclonal antibodies targeting PD-1 or PD-L1 are routinely used for the treatment of cancers, but their clinical efficacy varies largely across the variety of tumor types. A part of the variability is linked to the existence of several forms of PD-L1, either expressed on the plasma membrane (mPD-L1), at the surface of secreted cellular exosomes (exoPD-L1), in cell nuclei (nPD-L1), or as a circulating, soluble protein (sPD-L1). Here, we have reviewed the different origins and roles of sPD-L1 in humans to highlight the biochemical and functional heterogeneity of the soluble protein. sPD-L1 isoforms can be generated essentially by two non-exclusive processes: (i) proteolysis of m/exoPD-L1 by metalloproteases, such as metalloproteinases (MMP) and A disintegrin and metalloproteases (ADAM), which are capable of shedding membrane PD-L1 to release an active soluble form, and (ii) the alternative splicing of PD-L1 pre-mRNA, leading in some cases to the release of sPD-L1 protein isoforms lacking the transmembrane domain. The expression and secretion of sPD-L1 have been observed in a large variety of pathologies, well beyond cancer, notably in different pulmonary diseases, chronic inflammatory and autoimmune disorders, and viral diseases. The expression and role of sPD-L1 during pregnancy are also evoked. The structural heterogeneity of sPD-L1 proteins, and associated functional/cellular plurality, should be kept in mind when considering sPD-L1 as a biomarker or as a drug target. The membrane, exosomal and soluble forms of PD-L1 are all integral parts of the highly dynamic PD-1/PD-L1 signaling pathway, essential for immune-tolerance or immune-escape.

Keywords: PD-1/PD-L1; autoimmune diseases; cancer; immune checkpoint; immuno-suppression; protein maturation; soluble PD-L1.

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Conflict of interest statement

The author declares no conflict of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Figures

Figure 2
Figure 2
A non-exhaustive list of malignant and non-malignant diseases for which sPD-L1 has been measured in the plasma of patients. In most cases, the level of circulating sPD-L1 was found to be enhanced in the plasma of patients with the indicated pathology compared to healthy control (see Table 1. For the oncology indications, the presence of sPD-L1 and its significance are discussed in the following studies: AEC [41]; BTC [42,43]; brain tumors [26,44]; CRCC [45,46]; CRC [47]; cutaneous melanoma [48]; DLBCL [49,50]; EOC [51,52]; ENKTL [53,54]; HNSCC [36]; HCC [55,56,57]; HL [54,58]; mesothelioma [59,60]; NC [61,62]; PGC [63,64,65]; NSCLC [66,67]; PC [68]; PCNSL [50]; STS [69,70]; TC [71]; TNBC [72]; WM [73].
Figure 4
Figure 4
Alignment of amino acid sequences of PD-L1 from humans with other species. A stalk region of 10–12 amino acids (in bold blue) is located between the IgC-like domain and the transmembrane domain. This region would correspond to the site of cleavage of mPD-L1 by proteases, MMPs and/or ADAMs, to release sPD-L1 [83]. Amino acid sequences were derived from [86,87].
Figure 5
Figure 5
Two examples of alternative splicing of the PD-L1 pre-mRNA. The exons’ and introns’ organization of full-length PD-L1 is shown in the middle, and the full-length PD-L1 protein is shown on the right with its different domains (as in Figure 1). Above, the splice variant PD-L1-9, which has lost a 66-bp region from nt-725 to 790 in exon 4. The deletion indicates a frame shift leading to a stop codon before the transmembrane domain (TM). The variant produces a truncated sPD-L1 protein (38 kDa) lacking the TM and intracellular domains [48]. Below is an alternatively spliced form of the human PD-L1 cDNA from placental tissue. The variant contains the first 4 exons of PD-L1, including the secretory signal (SecSig) at the N-terminus, IgV and IgC domains, which are shared with the full-length PD-L1. The variant does not splice into the fifth exon (encoding the transmembrane domain) but reads into the fourth intron, within a new stop codon. It produces an mRNA that lacks a transmembrane domain at its 3′ end and leads to a protein with the indicated unique C-terminal sequence. The underlined cysteine residue (C239) allows for protein homodimerization, as represented on the right side. The expressed protein, naturally dimerizing, was found to inhibit T-cell proliferation and production of IFN-γ from activated T-cells [105].
Figure 1
Figure 1
The different forms of the checkpoint protein PD-L1: membrane form (mPD-L1) with its characteristic transmembrane domain (TM) and intracellular domain (ICD); the exosomal form (exoPD-L1) embarked into extracellular vesicles released by a variety of cells; the nuclear form (nPD-L1) involved in the regulation of mRNA stability; the soluble forms (sPD-L1), which can derive either from proteolytic cleavage of m/exoPD-L1 or from an alternative mRNA splicing. m/exo/sPD-L1 can modulate T-lymphocyte activity via the PD-1 signaling pathway.
Figure 3
Figure 3
PD-L1 primary structure and processing. (a) mPD-L1 with its IgV domain (which interacts with PD-1) and IgC domain linked to the transmembrane domain (TM) via a short flexible stalk. The TM domain is connected to the intracellular (ICD) domain. The molecular model of PD-L1 derives from the crystal structure of the free protein (PDB access code 3BIS). (b) Model of PD-1 interacting with PD-L1 via its IgV domain. (c) Primary structure of mPD-L1 with the different domains and sites of post-translational modifications (N-glycosylation at N35, N192, N200 and N219; phosphorylation at Y112, T180, S184, S195, ubiquitination at K178 and palmitoylation at C272). Proteolytic cleavage generally occurs within a short stalk region situated between the IgC and TM domains. (d) Representation of mPD-L1 shedding by different proteases (MMPs, ADAMs) to release a soluble form of PD-L1, which plays a role in cell signaling.
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