Soluble PD-L1: a potential immune marker for HIV-1 infection and virological failure

Avendaño-Ortíz, José; Rubio-Garrido, Marina; Lozano-Rodríguez, Roberto; Romero, Jorge del; Rodrı́guez, Carmen; Moreno, Santiago; Aguirre, Luis A.; Holguín, África; López-Collazo, Eduardo

doi:10.1097/md.0000000000020065

Cited by 13 publications

(14 citation statements)

References 25 publications

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“…To explore the origin of these differences, we studied soluble factors associated with immune cell exhaustion and immunosenescence. All MS patients showed a modest age-associated increase of PD-L1, a check point molecule capable of inducing T cell tolerization that rises in old individuals ( 29 ). This confirms the appearance of an early immunosenescence process in MS patients, since this study was performed in individuals aged between 16 and 65 years, an age at which most healthy individuals did not enter in the immunosenescence process yet.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

et al. 2021

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Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.

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Section: Discussionmentioning

confidence: 99%

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

et al. 2021

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“… [ 136 , 137 ] HIV-1 infection (AIDS) Much higher levels of sPD-L1 in HIV-infected patients compared to uninfected adults. [ 138 , 139 ] Acute respiratory distress syndrome (ARDS) sPD-L1 upregulated in survivors of direct ARDS compared to non-survivors. sPD-L1 induces apoptosis of monocyte-derived macrophages in ARDS patients.…”

Section: Soluble Pd-l1 Beyond Cancermentioning

confidence: 99%

“…Moreover, the levels of sPD-L1 were also high in individuals that do not respond to antiretroviral therapy. The circulating protein may thus be particularly useful to follow the treatment response in HIV patients [ 138 ]. In HIV-positive patients, the high level of sPD-L1 likely arises from mPD-L1 expressed on monocyte-derived dendritic cells, which at the same time present an elevated level of MMP-2, susceptible to produce sPD-L1 upon proteolysis [ 139 ].…”

Section: Soluble Pd-l1 Beyond Cancermentioning

confidence: 99%

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

Bailly

Thuru

Quesnel

2021

Cancers

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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.

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“…A recent study used ELISA to quantify plasma levels of sPD-L1 in PLHIV and healthy controls and found that plasma levels of sPD-L1 were significantly elevated in PLHIV and remained high despite control of HIV infection by ART 107 . In addition, PLHIV on ART with virological failure had the highest plasma levels of sPD-L1 107 . Thus, sPD-L1 in the peripheral blood represents a potential biomarker of immune exhaustion and virological failure in PLHIV.…”

Section: Soluble Immune Checkpoints In People Living With Hiv (Plhiv)mentioning

confidence: 99%

“…In addition to mICPs that have been demonstrated to play a critical role in immune homeostasis in PLHIV, sICPs may also be dysregulated in PLHIV and thereby contribute to immune exhaustion in PLHIV. A recent study used ELISA to quantify plasma levels of sPD-L1 in PLHIV and healthy controls and found that plasma levels of sPD-L1 were significantly elevated in PLHIV and remained high despite control of HIV infection by ART 107 . In addition, PLHIV on ART with virological failure had the highest plasma levels of sPD-L1 107 .…”

Section: Introductionmentioning

confidence: 99%

Soluble immune checkpoints are dysregulated in COVID-19 and heavy alcohol users with HIV infection

Syed

et al. 2021

Preprint

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Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the world's most serious public health challenges. A storm of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol abuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol abuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease.

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Soluble PD-L1: a potential immune marker for HIV-1 infection and virological failure

Cited by 13 publications

References 25 publications

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

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

Soluble immune checkpoints are dysregulated in COVID-19 and heavy alcohol users with HIV infection

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