NK cells-derived extracellular vesicles potency in the B cell lymphoma biotherapy

• Published in: Frontiers in immunology 2024, Vol.15, p.1503857
• Main Authors: Cecchetti, Serena, Federici, Cristina, Canese, Rossella, Iorio, Egidio, Huber, Veronica, Pisanu, Maria Elena, Chirico, Mattea, Iessi, Elisabetta, Camerini, Serena, Casella, Marialuisa, Matteucci, Andrea, Macchia, Daniele, Spada, Massimo, Lugini, Luana
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; B cell lymphoma; Cell Line, Tumor; exosomes; Exosomes - immunology; Exosomes - metabolism; extracellular vesicles; Extracellular Vesicles - immunology; Extracellular Vesicles - metabolism; Female; Humans; immunotherapy; Killer Cells, Natural - immunology; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - therapy; Mice; Mice, SCID; microvesicles; NK cells; Xenograft Model Antitumor Assays
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1503857

Extracellular vesicles of Natural Killer cells (NKEV) exert an antitumor effect towards hematopoietic and solid tumors and have an immune modulating effect, suggesting a promising role in immune and biotherapy. In this study, a continuation of our former works, we demonstrated a network by mass spectrometry analysis between NKEV protein cargo and antitumor effects. Human healthy NKEV, both exosomes and microvesicles, have a significant and direct cytotoxic effect against human B cell lymphoma in and conditions. We isolated extracellular vesicles from amplified healthy human NK cells and their treatment efficacy was monitored by cytometry analyses, MRI/MRS measurements, ex vivo MRS analyses and immunohistochemistry. We observed a remarkable NKEV cytotoxic effect, mainly by apoptosis, on B cell lymphoma when exosomes and microvesicles were administered simultaneously. results showed metabolic alterations in SCID mice xenografts after NKEV treatment, associated with a significant reduction of tumor growth (64%). In the H MR spectra we found a significant increase in the tumor lipid/lactate and in taurine signals, both considered as apotosis markers. Ex vivo lymphoma metabolomics revealed a significant increase in fatty acid (FA) pool and decrease in unsaturated and mono-unsaturated FA in treated groups, as compared to control one, thus suggesting an alteration of tumor homeostasis. Immunohistochemistry analyses confirmed the reduction of B-cell lymphoma proliferation rate, as well as the induction of apoptosis following the NKEV treatment. This study underscore the importance of NKEV as a novel biological acellular tool for B-cell lymphoma treatment, probably having a greater effect on combined treatment regimens. These nanovesicles have an extraordinary potential in innovative cancer immunotherapy, representing a safe and efficient tool naturally circulating in healthy individuals and ready to maintain the immune homeostasis, and therefore a good organism healthy state.