Regulation of PD-L1: a novel role of pro-survival signalling in cancer

Chen, Jiezhong; Jiang, Chen Chen; Jin, Lei; Zhang, Xu Dong

doi:10.1093/annonc/mdv615

Cited by 644 publications

(610 citation statements)

References 94 publications

(4 reference statements)

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“…3,4 IFNg, in turn, provokes the adaptive upregulation of the programmed death ligand 1 (PD-L1, also known as B7-H1) on nearby tumor cells via NFkB, 5 thereby mediating a negative feedback mechanism that ultimately leads to T-cell exhaustion in tumor-infiltrating lymphocytes. Upon binding of PD-L1 to its programmed death receptor (PD-1) on T lymphocytes, it limits the activity of the T-cell receptor (TCR) and thereby abolishes cytolytic activity.…”

Section: Introductionmentioning

confidence: 99%

PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients

et al. 2016

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This study evaluates promoter methylation of the programmed cell death ligand 1 (PD-L1) as a biomarker in a cohort of 383 colorectal cancer patients. PD-L1 methylation (mPD-L1) was inversely correlated with PD-L1 mRNA expression (p D 0.001) and was associated with significantly shorter overall survival (OS, p D 0.003) and recurrence-free survival (RFS, p < 0.001). In age-stratified multivariate Cox proportional hazards analyses including sex, tumor, nodal, distant metastasis categories, microsatellite instability (MSI)-status, and PD-L1 mRNA, mPD-L1 is classified as an independent prognostic factor (OS: p D 0.030; RFS: p < 0.001). Further studies are needed to evaluate PD-L1 methylation as a biomarker for response prediction of immunotherapies targeting the PD-1/PD-L1 axis.

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Section: Introductionmentioning

confidence: 99%

PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients

et al. 2016

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“…Induced PD-L1 upregulation is regulated by various other cytokines, such as IFN, Tumor necrosis factor (TNF)-α and Toll-like receptor (TLR) etc. [60]. Most importantly, PD-L1 upregulation can also improve survival of mice with lung tumor, which received anti-PD-L1 treatment [61].…”

Section: Role Of Pd-l1 In Efficacy Of Treatmentmentioning

confidence: 99%

The function and regulation of PD-L1 in immunotherapy

Guo¹,

Lin²,

Kwok³

2017

ADMET DMPK

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PD-L1, also known as B7-H1, is a type I transmembrane protein, which is expressed in different kinds of tumor cells. It is correlated with poor clinical outcome of patients with various types of tumors. PD-L1 can regulate tumor microenvironment or tumor related immune response through suppressing T cell or NK cell mediated immune response. PD-L1 expression is regulated by various cytokines, such as LPS, GM-CSF, IL-4, TGF-β, TNF-α. PD-1 and PD-L1 are the members of B7 and CD28 superfamily, respectively. The B7/CD28 interaction plays a central role in immune tolerance. PD-L1 can bind to PD-1, which leads to the suppression of lymphocyte activation and apoptosis of lymphocytes. Anti-PD-L1 therapy is one of the immunotherapies to treat cancer (especially solid tumor). PD-L1 expression may be associated with efficacy

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“…PD-1 has two ligands, PD-L1 and PD-L-2, both of which are members of the B7 family of transmembrane proteins [26] . While the expression of PD-L2 is largely restricted to antigen-presenting cells, PD-L1 is expressed on many cell types such as APCs, B-cells, T-cells, epithelial cells, and monocytes, and is upregulated in response to proinflammatory cytokines such as IFN- and IL-4 through signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1) [26] .…”

Section: Nivolumab Biomarkersmentioning

confidence: 99%

“…While the expression of PD-L2 is largely restricted to antigen-presenting cells, PD-L1 is expressed on many cell types such as APCs, B-cells, T-cells, epithelial cells, and monocytes, and is upregulated in response to proinflammatory cytokines such as IFN- and IL-4 through signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1) [26] . Unfortunately, PD-L1 is currently a weak biomarker in clinical practice due to (a) expression levels: tumors with higher expression of PD-L1 often correlate with poor prognosis in several malignant tumors as compared to tumors with low expression of PD-L1 [27] ;…”

Section: Nivolumab Biomarkersmentioning

confidence: 99%

“…(b) tumor heterogeneity: there are wide intra-and inter-tumoral variations in the expression of PD-L1, indicating that sampling of tumor tissues may also impinge on the outcome of PD-L1 detection [26] ; (c) low specificity: tumors that do not express detectable levels of PD-L1 on the cell surface can also respond to antibodies against PD-1, suggesting that the predictive value of PD-L1 expression may not be uniformly applicable to all types of cancer [26] ; (d) inducible gene expression: PD-L1 can be expressed constitutively or can be induced by IFN- [28,29] secreted by infiltrating lymphocytes or by IL-27 [30] ; and (e ) potential drug resistance: resistance to PD-L1 inhibitors may be a cause of therapeutic failure, however, this has not been well-studied at the current time and needs systematic investigation [26] . PD-L1 has been reported to be modulated by MAPK and PI3K/AkT/mTOR oncogenic signaling pathways [31,32] .…”

Section: Nivolumab Biomarkersmentioning

confidence: 99%

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Pharmacometrics and systems pharmacology of immune checkpoint inhibitor nivolumab in cancer translational medicine

Nair

2016

Adv Mod Oncol Res

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Nivolumab, a fully human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) that targets the programmed cell death-1 (PD-1) inhibitory receptor expressed on lymphocytes and dendritic cells, has been approved for metastatic melanoma, advanced squamous non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma. In this review, systems pharmacology and pharmacometrics of this immunopharmaceutical are discussed. Mechanistic actions of T-cell biology with respect to both "priming phase" (anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) mAb; ipilimumab) and "effector phase" (anti-PD-1 mAb; nivolumab) are discussed, respectively. Key pharmacometric variables in anticancer efficacy of nivolumab such as target engagement, metabolism, pharmacology systems and clearance are elucidated with an emphasis on current knowledge from pre-clinical as well as phase 1, 2 and 3 clinical trials, including the data presented at the American Society of Clinical Oncology (ASCO) 2015 and European Cancer Congress 2015. Nivolumab biomarkers, safety, and synergistic combination immunotherapies are delineated. Nivolumab, administered via intravenous infusion, has an acceptable safety profile and good efficacy. Indeed, the way forward to leverage maximum benefits for the cancer patient may be to synergize anti-PD-1 blockade with complementary targets in immune checkpoint pathways or other oncogenic signal transduction pathways. The encouraging results with nivolumab lend credence to the promise of immune checkpoint blockade as a therapeutic strategy that has come of age in clinical oncology. Of necessity, the burden of "financial toxicity" on cancer patients and families must be factored in considering nivolumab therapy. The problem of ligand PD-L1 being a weak biomarker in clinical practice is discussed. Appropriate patient selection methods including immunopharmacogenomics may be used to identify those patients who are most likely to benefit from anti-PD-1 therapy. Taken together, the potential success of nivolumab strengthens the case for accelerated development of immunopharmaceuticals and basic drug discovery in oncology, and potentially non-oncology indications, by stakeholders such as clinical oncologists, pharmacists and scientists in academia and the pharmaceutical industry in a concerted fashion.Keywords: Nivolumab; PD-1; cancer; biomarkers; pharmacometrics; systems pharmacology; pharmacokinetics; T-cell; translational medicine Citation: Nair S. Pharmacometrics and systems pharmacology of immune checkpoint inhibitor nivolumab in cancer translational medicine. Adv Mod Oncol Res 2016; 2(1): 18-31; http://dx

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Regulation of PD-L1: a novel role of pro-survival signalling in cancer

Cited by 644 publications

References 94 publications

PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients

PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients

The function and regulation of PD-L1 in immunotherapy

Pharmacometrics and systems pharmacology of immune checkpoint inhibitor nivolumab in cancer translational medicine

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