The immunomodulatory ballet of tumour‐derived extracellular vesicles and neutrophils orchestrating the dynamic CD73/PD‐L1 pathway in cancer

• DOI: 10.1002/jev2.12480
• Publication Date: 2024-07-09T05:38:03Z
• Authors: Dominique S. Rube...; Jordana L. Domaga...; Gabriela F. S. Ge...; Jonas Eichberger; Mathias Fiedler; Florian Weber; Marianne Federlin; Hendrik Poeck; Torsten E. Reichert; Tobias Ettl; Richard J. Bauer; Elizandra Braganhol; Daniela Schulz
• Keywords: Immune checkpoint; Cancer Immunotherapy

Abstract Head and neck squamous cell carcinoma (HNSCC) is a global cancer burden with 5‐year overall survival rate of around 50%, stagnant for decades. A tumour‐induced immunosuppressive microenvironment contributes to HNSCC progression, the adenosine (ADO) pathway an upregulated expression inhibitory immune checkpoint regulators playing key role in this context. The correlation between high neutrophil‐to‐lymphocyte ratio (NLR) advanced tumour staging suggests involvement neutrophils (NØ) progression. Interestingly, we associated NLR increased intracellular PD‐L1 localization primary samples, potentially mediating more aggressive characteristics therefore synergistically favouring Still, further research needed harness knowledge effective treatments overcome resistance. Since it hypothesized that (TME) may be influenced by small extracellular vesicles (sEVs) secreted tumours (TEX), study aims investigate impact HNSCC‐derived TEX on NØ blockade ADO receptors as potential strategy reverse pro‐tumour phenotype NØ. UMSCC47‐TEX exhibited CD73 enzymatic activity involved signalling, well inhibitor PD‐L1. Data revealed induce chemotaxis sustained interaction promotes shift into phenotype, dependent (P1R), increasing CD170 subpopulation, expression, followed secretome. Blocking A3R reduced expression. Co‐culture experiments cells demonstrated TEX‐modulated increase CD73/PD‐L1 axis, through Cyclin D‐CDK4/6 signalling. To support these findings, CAM model was treated supernatant. Moreover, promoted migration, invasion, death. Targeting P1R NØ, particularly A3R, therapeutic counteract immunosuppression HNSCC. Understanding TEX‐mediated crosstalk offers insights immunomodulation improving therapies.