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

Simple Summary The interaction of programmed cell death ligand-1 (PDL1) with its receptor PD1 inhibits T-cell responses. Blockade of this interaction with monoclonal antibodies leads to major antitumor effects. However, not all cancer patients respond well to anti-(PD-1/PD-L1) immunotherapy. The PD-L1 protein is expressed at the cell plasma membrane (mPD-L1), at the surface of exosomes (exoPD-L1), in cell nuclei (nPD-L1) and as a soluble circulating protein (sPD-L1). The aim of our analysis was to highlight the multiple variants of sPD-L1 generated either by the proteolytic cleavage of m/exoPD-L1 or by the alternative splicing of PD-L1 pre-mRNA. The objective was also to underline the presence and role of circulating sPD-L1 isoforms in multiple cancer indications and many other diseases (including chronic inflammatory and viral diseases), and under non-pathological conditions (pregnancy). sPD-L1 often represents a general marker of an inflammatory status. The pool of sPD-L1 proteins is an integral part of the highly dynamic PD-1/PD-L1 signaling pathway. 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.