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

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.

Time-Dependent Efficacy of Checkpoint Inhibitor Nivolumab: Results from a Pilot Study in Patients with Metastatic Non-Small-Cell Lung Cancer

“…The reduced activity of afternoon nivolumab could involve the exacerbation of resistance mechanisms in this temporal window, including defective antigen presentation processes, multiple immune checkpoint interactions, transient refractoriness of the tumoral immune microenvironment, activation of oncogenic pathways, and epigenetic changes of key proteins in tumors, among other factors [ 51 , 52 ]. Nivolumab could also become inactivated shortly after its infusion through binding to circulating proteins or extracellular vesicles [ 53 , 54 ], thus accounting for consistent resistance in the ‘afternoon’ group in the landmark analyses. In general, the relevance of dosing time for cancer treatments has been underestimated in oncology, with temporal logistics organization of hospitals predominating over temporal changes in biological functions.…”

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

“…However, a negative effect of this treatment is that the PD-1/PD-L1 blockade may induce autoreactive T cells responsible for immune-related adverse effects (irAEs) [58]. In addition, recent evidence suggests that one of the molecular mechanisms responsible for the failure of PD-1/PD-L1 targeted therapy is the presence of extra-tumoral PD-L1 contained in exosomes, small nanoparticles released from the surface of both normal and tumor cells containing biologically active molecules [59]. Exosomes may release pro-tumoral signaling molecules in cancer.…”

“…Exosomes may release pro-tumoral signaling molecules in cancer. Preclinical and clinical evidence has associated the presence of PD-L1-containing exosomes with an immunosuppressive TIME and with a worse prognosis in several cancers [59]. In addition, PD-L1-containing exosomes could contribute to PD-1-specific mAb treatment resistance.…”

Importance of Efferocytosis in COVID-19 Mortality

“… 80 Although circulating soluble PD-L1 (sPD-L1) has been largely known as a prognostic biomarker for cancers, 81 sPD-L1 has also been detected in various pathologies, often associated with markers of inflammation. 82 Of note, a recent study suggests that an increase in sPD-L1 may be a sign of poor prognosis as a result of dysregulation of the PD-1/PD-L1 axis in COVID-19 patients. 83 …”