A snapshot of the PD-1/PD-L1 pathway

Ghosh, Chinmoy; Luong, Gary; Sun, Yue

doi:10.7150/jca.57334

Cited by 153 publications

(136 citation statements)

References 148 publications

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“…In addition, PD-L1 (CD274, B7-H1) plays a key role as a negative regulator of antitumor immunity, and the blockade of the PD-1/PD-L1 interaction permits one to restore and to increase the function of T-cells. Monoclonal antibodies directed against PD-1 (Nivolumab, Pembrolizumab, Cemiplimab, Spartalizumab, Camrelizumab, Sintilimab) or PD-L1 (Atezolizumab, Durvalumab, Avelumab, SHR-1316) are now used regularly for the treatment of multiple types of solid tumors, such as non-small cell lung cancer (NSCLC), melanoma, and gastric cancers to cite only a few types [ 1 ]. Since the first approval of pembrolizumab in 2014 for the treatment of advanced or unresectable melanoma, seven antibodies targeting PD-1 or PD-L1 have been approved by the Food and Drug Administration (FDA) for the treatment of solid tumors or onco-hematological diseases (lymphoma) [ 2 ].…”

Section: The Pd-1/pd-l1 Checkpointmentioning

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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Section: The Pd-1/pd-l1 Checkpointmentioning

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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“…During an immune response, PD-1 is transiently expressed on CD4+ and CD8+ T cells, B cells, natural killer (NK) cells, monocytes, dendritic cells (DCs), and tumor-infiltrating lymphocytes (TILs) [ 13 , 14 ]. TCR engagement and cytokine stimulation, including interleukin (IL)-2, IL-7, IL-15, IL-21, tumor necrosis factor-α (TNFα) and interferon gamma (IFNγ), induce PD-1 expression following antigenic stimulation, which then decreases when the antigen stimulus stops [ 15 , 16 , 17 ]. PD-1 expression is also modulated by glycolysis, which downregulates PD-1 in CD4+ T cells.…”

Section: Pd-1/pd-l1 In Health and Cancermentioning

confidence: 99%

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

Adorisio

Cannarile

Delfino

et al. 2021

Cells

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Programmed cell death protein 1 (PD-1) and its ligands, PD-L1/2, control T cell activation and tolerance. While PD-1 expression is induced upon T cell receptor (TCR) activation or cytokine signaling, PD-L1 is expressed on B cells, antigen presenting cells, and on non-immune tissues, including cancer cells. Importantly, PD-L1 binding inhibits T cell activation. Therefore, the modulation of PD-1/PD-L1 expression on immune cells, both circulating or in a tumor microenvironment and/or on the tumor cell surface, is one mechanism of cancer immune evasion. Therapies that target PD-1/PD-L1, blocking the T cell-cancer cell interaction, have been successful in patients with various types of cancer. Glucocorticoids (GCs) are often administered to manage the side effects of chemo- or immuno-therapy, exerting a wide range of immunosuppressive and anti-inflammatory effects. However, GCs may also have tumor-promoting effects, interfering with therapy. In this review, we examine GC signaling and how it intersects with PD-1/PD-L1 pathways, including a discussion on the potential for GC- and PD-1/PD-L1-targeted therapies to “confuse” the immune system, leading to a cancer cell advantage that counteracts anti-cancer immunotherapy. Therefore, combination therapies should be utilized with an awareness of the potential for opposing effects on the immune system.

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“…While playing a key role in physiological immune homeostasis, the PD-1/PD-L1 axis also putatively serves as a means through which cancer cells evade the immune system. In human neoplasia, PD-L1 is reported to be expressed by tumor cells, whereas PD-1 is generally expressed by tumor-infiltrating lymphocytes (TIL), and their interaction negatively regulates the adaptive antitumor immune response [ 10 ]. The development of anti-PD-1/PD-L1 monoclonal antibodies has recently become a hot topic in cancer immunotherapy, thereby dramatically changing the therapeutic approaches for many cancers at an advanced stage [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of PD-L1, PD-1 and CD8A in Canine Diffuse Large B-Cell Lymphoma Detected by RNAscope

Aresu

Marconato

Martini

et al. 2021

Veterinary Sciences

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Immune checkpoints are a set of molecules dysregulated in several human and canine cancers and aberrations of the PD-1/PD-L1 axis are often correlated with a worse prognosis. To gain an insight into the role of immune checkpoints in canine diffuse large B-cell lymphoma (cDLBCL), we investigated PD-L1, PD-1 and CD8A expression by RNAscope. Results were correlated with several clinico-pathological features, including treatment, Ki67 index and outcome. A total of 33 dogs treated with chemotherapy (n = 12) or chemoimmunotherapy with APAVAC (n = 21) were included. PD-L1 signal was diffusely distributed among neoplastic cells, whereas PD-1 and CD8A were localized in tumor infiltrating lymphocytes. However, PD-1 mRNA was also retrieved in tumor cells. An association between PD-L1 and PD-1 scores was identified and a higher risk of relapse and lymphoma-related death was found in dogs treated with chemotherapy alone and dogs with higher PD-L1 and PD-1 scores. The correlation between PD-L1 and PD-1 is in line with the mechanism of immune checkpoints in cancers, where neoplastic cells overexpress PD-L1 that, in turn, binds PD-1 receptors in activated TIL. We also found that Ki67 index was significantly increased in dogs with the highest PD-L1 and PD-1 scores, indirectly suggesting a role in promoting tumor proliferation. Finally, even if the biological consequence of PD-1+ tumor cells is unknown, our findings suggest that PD-1 intrinsic expression in cDLBCL might contribute to tumor growth escaping adaptive immunity.

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A snapshot of the PD-1/PD-L1 pathway

Cited by 153 publications

References 148 publications

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

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

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

Prognostic Value of PD-L1, PD-1 and CD8A in Canine Diffuse Large B-Cell Lymphoma Detected by RNAscope

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