Rubenich, Dominique S. and Domagalski, Jordana L. and Gentil, Gabriela F. S. and Eichberger, Jonas and Fiedler, Mathias and Weber, Florian and Federlin, Marianne and Poeck, Hendrik and Reichert, Torsten E. and Ettl, Tobias and Bauer, Richard J. and Braganhol, Elizandra and Schulz, Daniela (2024) The immunomodulatory ballet of tumour-derived extracellular vesicles and neutrophils orchestrating the dynamic CD73/PD-L1 pathway in cancer. JOURNAL OF EXTRACELLULAR VESICLES, 13 (7): e2480. ISSN , 2001-3078
Full text not available from this repository. (Request a copy)Abstract
Head and neck squamous cell carcinoma (HNSCC) is a global cancer burden with a 5-year overall survival rate of around 50%, stagnant for decades. A tumour-induced immunosuppressive microenvironment contributes to HNSCC progression, with the adenosine (ADO) pathway and an upregulated expression of inhibitory immune checkpoint regulators playing a key role in this context. The correlation between high neutrophil-to-lymphocyte ratio (NLR) with advanced tumour staging suggests involvement of neutrophils (N & Oslash;) in cancer progression. Interestingly, we associated a high NLR with an increased intracellular PD-L1 localization in primary HNSCC samples, potentially mediating more aggressive tumour characteristics and therefore synergistically favouring tumour progression. Still, further research is needed to harness this knowledge for effective treatments and overcome resistance. Since it is hypothesized that the tumour microenvironment (TME) may be influenced by small extracellular vesicles (sEVs) secreted by tumours (TEX), this study aims to investigate the impact of HNSCC-derived TEX on N & Oslash; and blockade of ADO receptors as a potential strategy to reverse the pro-tumour phenotype of N & Oslash;. UMSCC47-TEX exhibited CD73 enzymatic activity involved in ADO signalling, as well as the immune checkpoint inhibitor PD-L1. Data revealed that TEX induce chemotaxis of N & Oslash; and the sustained interaction promotes a shift into a pro-tumour phenotype, dependent on ADO receptors (P1R), increasing CD170high subpopulation, CD73 and PD-L1 expression, followed by an immunosuppressive secretome. Blocking A3R reduced CD73 and PD-L1 expression. Co-culture experiments with HNSCC cells demonstrated that TEX-modulated N & Oslash; increase the CD73/PD-L1 axis, through Cyclin D-CDK4/6 signalling. To support these findings, the CAM model with primary tumour was treated with N & Oslash; supernatant. Moreover, these N & Oslash; promoted an increase in migration, invasion, and reduced cell death. Targeting P1R on N & Oslash;, particularly A3R, exhibited potential therapeutic strategy to counteract immunosuppression in HNSCC. Understanding the TEX-mediated crosstalk between tumours and N & Oslash; offers insights into immunomodulation for improving cancer therapies. The interaction between tumor and neutrophils via tumor-derived exosomes (TEX) involves adenosine signaling, influencing neutrophil responses towards a pro-tumor phenotype, by increasing CD170highsubpopulation, CD73 and PD-L1expression. This modulation in turn induces increased expression of CD73/PD-L1 pathway on tumor cells, thereby promoting disease progression. Impairment of adenosine signaling in neutrophils results in varying phenotypic changes, dependent on the activation of specific adenosine receptors that can either synergistically enhance (A2BR) or inhibit (A3R) TEX-mediated modulation. image
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SQUAMOUS-CELL CARCINOMA; EMERGING ROLE; EXOSOMES; PD-L1; PROGRESSION; HEAD; MACROPHAGES; PD-1/PD-L1; RESISTANCE; CD39; adenosine signalling; biomarker; cytoplasmatic PD-L1; exosome; head and neck squamous cell carcinoma; immune checkpoint resistance; tumour-associated neutrophils (TAN) |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Mund-, Kiefer- und Gesichtschirurgie Medicine > Lehrstuhl für Pathologie Medicine > Lehrstuhl für Zahnerhaltung und Parodontologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Jul 2025 09:00 |
| Last Modified: | 22 Jul 2025 09:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/63610 |
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