Programmed Death Ligand 1
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Yutaka Matsubara ◽  
Luis Gonzalez ◽  
Gathe Kiwan ◽  
Jia Liu ◽  
John Langford ◽  

Objective: Patients with end-stage renal disease depend on hemodialysis for survival. Although arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, the primary success rate of AVF is only 30% to 50% within 6 months, showing an urgent need for improvement. PD-L1 (programmed death ligand 1) is a ligand that regulates T-cell activity. Since T cells have an important role during AVF maturation, we hypothesized that PD-L1 regulates T cells to control venous remodeling that occurs during AVF maturation. Approach and results: In the mouse aortocaval fistula model, anti-PD-L1 antibody (200 mg, 3×/wk intraperitoneal) was given to inhibit PD-L1 activity during AVF maturation. Inhibition of PD-L1 increased T-helper type 1 cells and T-helper type 2 cells but reduced regulatory T cells to increase M1-type macrophages and reduce M2-type macrophages; these changes were associated with reduced vascular wall thickening and reduced AVF patency. Inhibition of PD-L1 also inhibited smooth muscle cell proliferation and increased endothelial dysfunction. The effects of anti-PD-L1 antibody on adaptive venous remodeling were diminished in nude mice; however, they were restored after T-cell transfer into nude mice, indicating the effects of anti-PD-L1 antibody on venous remodeling were dependent on T cells. Conclusions: Regulation of PD-L1 activity may be a potential therapeutic target for clinical translation to improve AVF maturation.

Bo Shao ◽  
Qin Dang ◽  
Zhuang Chen ◽  
Chen Chen ◽  
Quanbo Zhou ◽  

Programmed death ligand 1 (PD-L1) is a typical immune surface protein that binds to programmed cell death 1 (PD-1) on T cells through its extracellular domain. Subsequently, T cell activity is inhibited, and tumor immune tolerance is enhanced. Anti-PD-1/PD-L1 immune checkpoint therapy blocks the combination of PD-1/PD-L1 and rejuvenates depleted T cells, thereby inhibiting tumor growth. Exosomes are biologically active lipid bilayer nanovesicles secreted by various cell types, which mediate signal communication between cells. Studies have shown that PD-L1 can not only be expressed on the surface of tumor cells, immune cells, and other cells in the tumor microenvironment, but also be released from tumor cells and exist in an extracellular form. In particular, exosome PD-L1 plays an unfavorable role in tumor immunosuppression. The immunomodulatory effect of exosome PD-L1 and its potential in fluid diagnosis have attracted our attention. This review aims to summarize the available evidence regarding the biological characteristics of exosome PD-L1 in tumor immunity, with a particular focus on the mechanisms in different cancers and clinical prospects. In addition, we also summarized the current possible and effective detection methods for exosome PD-L1 and proposed that exosome PD-L1 has the potential to become a target for overcoming anti-PD-1/PD-L1 antibody treatment resistance.

Dina Mohamed El Samman ◽  
Manal Mohamed El Mahdy ◽  
Hala Sobhy Cousha ◽  
Zeinab Abd El Rahman Kamar ◽  
Khaled Abdel Karim Mohamed ◽  

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A17.3-A18
J Laengle ◽  
D Tamandl ◽  
R Schmid ◽  
J Widder ◽  
M Bergmann ◽  

BackgroundImmune checkpoint inhibitors (ICI), such as atezolizumab (anti-programmed death-ligand 1; PD-L1), have been proven to be an effective strategy in solid cancers. However, the overall response rate to ICI is currently limited to an intrinsically responsive tumor immune microenvironment (TIME) or depended on an appropriate foregone immune stimulus, such as radiotherapy. The concept of combining radiotherapy with ICI is currently investigated in a variety of solid cancers. However, little data is known on the expression dynamics of immune checkpoint ligands, such as PD-L1, during neoadjuvant chemoradiotherapy (CRT) or short-course preoperative radiotherapy (SCPRT) in human solid malignancies.Materials and MethodsThis is a prospective non-randomized open-label single-center investigator-initiated pilot study (NCT no. NCT04564482). Patients with either rectal cancer (RC), oesophageal adenocarcinoma (EAC), gastroesophageal junction (GEJ) cancer or oesophageal squamous cell carcinoma (ESCC), whom are assigned by the routine multidisciplinary tumor board (MDT) to receive a standard neoadjuvant CRT/SCPRT, will be enrolled. Standard neoadjuvant regimens include CRT (50 Gy in 2 Gy fractions over 25 working days + capecitabine 1650 mg/m2/d PO) or SCPRT (25 Gy in 5 Gy fractions over 5 working days) for RC patients and CRT according to the CROSS protocol (41.4 Gy in 1.8 Gy fractions over 23 working days + carboplatin AUC of 2 mg/ml/min + paclitaxel 50 mg/m2 IV Q1W) for patients with EAC, ESCC or GEJ cancer. Patients will receive a PD-L1 (89Zr-atezolizumab) positron emission tomography (PET) CT (for EAC, ESCC or GEJ cancers) or MRI (for RC) bevor (day 0) and during neoadjuvant treatment (day 10-14).ResultsThe primary endpoint of this pilot study is the none-invasive assessment of PD-L1 expression dynamics during neoadjuvant CRT/SCPRT by a PD-L1 PET imaging approach. Secondary objectives are the correlation between PD-L1 PET expression dynamics and radiographic as well as pathological therapy response.ConclusionsThis is the first in human study, which assesses PD-L1 expression dynamics during different neoadjuvant radiotherapeutic regimens. A detailed understanding of the impact of radiotherapy on PD-L1 expression, monitored by an none-invasive PET imaging approach, allows the application of radiotherapy as part of a novel immunotherapeutic concept.Disclosure InformationJ. Laengle: None. D. Tamandl: None. R. Schmid: None. J. Widder: None. M. Bergmann: None. A. Haug: None.

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