Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases.
TLDR
In this article, the authors reviewed the different origins and roles of sPD-L1 in humans to highlight the biochemical and functional heterogeneity of the soluble protein, and the structural heterogeneity of s PD-L 1 proteins should be kept in mind when considering sPDL1 as a biomarker or as a drug target.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.read more
Citations
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Exosomal CD73 from serum of patients with melanoma suppresses lymphocyte functions and is associated with therapy resistance to anti-PD-1 agents
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Non-coding RNAs and macrophage interaction in tumor progression.
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TL;DR: In this paper , the role of non-coding RNAs (ncRNAs) and exosomal ncRNAs derived from tumor cells or macrophages can be considered as non-invasive biomarkers for tumor diagnosis.
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Microglial PD-1 stimulation by astrocytic PD-L1 suppresses neuroinflammation and Alzheimer's disease pathology.
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Time-Dependent Efficacy of Checkpoint Inhibitor Nivolumab: Results from a Pilot Study in Patients with Metastatic Non-Small-Cell Lung Cancer
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References
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Exosomal PD-L1 Contributes to Immunosuppression and is Associated with anti-PD-1 Response
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TL;DR: The functions of exosomes in cancer development, metastasis, and anti-Tumor or pro-tumor immunity, plus their application in cancer treatment and diagnosis/prognosis are summarized.
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Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma
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Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade.
Jun Zhou,Kathleen M. Mahoney,Kathleen M. Mahoney,Anita Giobbie-Hurder,Fengmin Zhao,Sandra J. Lee,Xiaoyun Liao,Xiaoyun Liao,Scott J. Rodig,Scott J. Rodig,Jingjing Li,Xinqi Wu,Lisa H. Butterfield,Matthias Piesche,Matthias Piesche,Michael Manos,Lauren Eastman,Glenn Dranoff,Gordon J. Freeman,F. Stephen Hodi +19 more
TL;DR: Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors, and after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD -L1 had greater likelihood of developing a partial response.