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Πέμπτη 30 Μαΐου 2019

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.[5] Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the adaptive arm of immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the adaptive immune system reacts to antigens that are associated with immune system activation by exogenous or endogenous danger signals. In turn, clonal expansion of antigen-specific CD8+ T cells and/or CD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM) motif [6]. This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells) - further mediated by a lower regulation of the gene Bcl-2.Cancer Micrograph showing a PD-L1 positive lung adenocarcinoma. PD-L1 immunostain. It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of 196 tumor specimens from patients with renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death.[20] Many PD-L1 inhibitors are in development as immuno-oncology therapies and are showing good results in clinical trials.[21] Clinically available examples include Durvalumab, atezolizumab and avelumab.[22] In normal tissue, feedback between transcription factors like STAT3 and NF-κB restricts the immune response to protect host tissue and limit inflammation. In cancer, loss of feedback restriction between transcription factors can lead to increased local PD-L1 expression, which could limit the effectiveness of systemic treatment with agents targeting PD-L1. [23] Listeria monocytogenes In a mouse model of intracellular infection, L. monocytogenes induced PD-L1 protein expression in T cells, NK cells, and macrophages. PD-L1 blockade (using blocking antibodies) resulted in increased mortality for infected mice. Blockade reduced TNFα and nitric oxide production by macrophages, reduced granzyme B production by NK cells, and decreased proliferation of L. monocytogenes antigen-specific CD8 T cells (but not CD4 T cells).[24] This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection. Autoimmunity The PD-1/PD-L1 interaction is implicated in autoimmunity from several lines of evidence. NOD mice, an animal model for autoimmunity that exhibit a susceptibility to spontaneous development of type I diabetes and other autoimmune diseases, have been shown to develop precipitated onset of diabetes from blockade of PD-1 or PD-L1 (but not PD-L2).[25] In humans, PD-L1 was found to have altered expression in pediatric patients with Systemic lupus erythematosus (SLE). Studying isolated PBMC from healthy children, immature myeloid dendritic cells and monocytes expressed little PD-L1 at initial isolation, but spontaneously up-regulated PD-L1 by 24 hours. In contrast, both mDC and monocytes from patients with active SLE failed to upregulate PD-L1 over a 5-day time course, expressing this protein only during disease remissions.[26] This may be one mechanism whereby peripheral tolerance is lost in SLE.

Biomarkers

Molecular markers used to guide treatment, assess prognosis, or detect relapse.

PD-L1

The companies are using Strata's biomarker technology to identify genomic subpopulations of cancer patients who respond to Arcus' investigational immunotherapy drug.
The diagnostic can now be used to identify a wider range of patients with stage III or metastatic NSCLC who may benefit from first-line treatment with Keytruda.
In the JAMA study, researchers confirmed the previously known clinical and genomic features of NSCLC patients in their large clinico-genomics database.
Efforts highlighted at last week's AACR meeting included new efforts to advance gene expression signatures, improve PD-L1 tests, and calculate MSI across tumor types.
MSK researchers showed that high TMB may be associated with improved survival across tumor types, but the cut-offs for high and low status will vary based on histology.
New data on Kadcyla and Tecentriq will help doctors further refine precision medicine options for breast cancer patients with unmet needs.
Physicians can now use the Dako PD-L1 IHC 22C3 pharmDx assay to identify urothelial carcinoma patients who may benefit from the anti-PD1 immunotherapy.
With sequence data for more than 118,000 tumors profiled at Foundation Medicine, investigators tracked PDL1 amplification prevalence and possible treatment implications.
At ASCO, researchers presented on the WINTHER trial, which despite setbacks showed that both DNA and RNA analysis can be used to guide personalized treatment strategies.
Presentations largely reflected negatively on the utility of PD-L1 for stratifying response, but pivotal new data on tumor mutational burden as assessed by Foundation Medicine's genomic sequencing panel.

PD-L1

Patients with PD-L1-expressing gastric or gastroesophageal junction tumors can now be identified for potential treatment with Keytruda using Agilent's assay.
The changes include recommendations for first line immunotherapy in patients with high PD-L1 expression, and clarification on use of targeted therapies.
Collaborators have created an atlas that compares available PD-L1 IHC assays and reveals areas of debate, including challenges encountered by clinicians.
The Ventana PD-L1 assay was approved as a complementary diagnostic for bladder cancer patients being considered for treatment with the immunotherapy Imfinzi. 
The recent failure of Bristol-Myers Squibb's lung cancer immunotherapy to meet its primary endpoint demonstrates the challenge of working with imperfect biomarkers.
Looking beyond PD-L1 expression, investigators from several clinical trials considered a range of potential biomarkers for immune checkpoint treatment response.
The test, when used as intended, allows doctors to gauge the magnitude of benefit melanoma patients might derive from the immunotherapeutic Opdivo.
Dako developed the PD-L1 CDx very specifically to fit Keytruda's mechanism and patients' outcomes to the drug.
Clinical application of PD-L1 expression as a predictive marker won't be so straightforward because some patients with low expression also have a degree of response to Keytruda.

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