Nasopharyngeal carcinoma-derived small extracellular vesicles (NPCSEVs) have an immunosuppressive impact on the tumour microenvironment. In this study, we investigated their influence on the generation of tolerogenic dendritic cells and the potential involvement of the galectin-9 (Gal9) they carry in this process. We analysed the phenotype and immunosuppressive properties of NPCSEVs and explored the ability of DCs exposed to NPCSEVs (NPCSEV-DCs) to regulate T cell proliferation. To assess their impact at the pathophysiological level, we performed real-time fluorescent chemoattraction assays. Finally, we analysed phenotype and immunosuppressive functions of NPCSEV-DCs using a proprietary anti-Gal9 neutralising antibody to assess the role of Gal9 in this effect. We described that NPCSEV-DCs were able to inhibit T cell proliferation despite their mature phenotype. These mature regulatory DCs (mregDCs) have a specific oxidative metabolism and secrete high levels of IL-4. Chemoattraction assays revealed that NPCSEVs could preferentially recruit NPCSEV-DCs. Finally, and very interestingly, the reduction of the immunosuppressive function of NPCSEV-DCs using an anti-Gal9 antibody clearly suggested an important role for vesicular Gal9 in the induction of mregDCs. These results revealed for the first time that NPCSEVs promote the emergence of mregDCs using a galectin-9 dependent mechanism and open new perspectives for antitumour immunotherapy targeting NPCSEVs.

中文翻译：

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源自鼻咽癌的细胞外囊泡利用半乳糖凝集素 9 依赖性机制诱导成熟调节性树突状细胞的出现

鼻咽癌来源的小细胞外囊泡（NPCSEV）对肿瘤微环境具有免疫抑制作用。在这项研究中，我们研究了它们对耐受性树突状细胞生成的影响以及它们携带的半乳糖凝集素 9 (Gal9) 在此过程中的潜在参与。我们分析了 NPCSEV 的表型和免疫抑制特性，并探讨了暴露于 NPCSEV 的 DC（NPCSEV-DC）调节 T 细胞增殖的能力。为了评估它们在病理生理水平上的影响，我们进行了实时荧光化学吸引测定。最后，我们使用专有的抗 Gal9 中和抗体分析了 NPCSEV-DC 的表型和免疫抑制功能，以评估 Gal9 在这种效应中的作用。我们描述了 NPCSEV-DCs 能够抑制 T 细胞增殖，尽管它们具有成熟的表型。这些成熟的调节性 DC (mregDC) 具有特定的氧化代谢并分泌高水平的 IL-4。化学吸引试验表明 NPCSEV 可以优先招募 NPCSEV-DC。最后，非常有趣的是，使用抗 Gal9 抗体降低 NPCSEV-DC 的免疫抑制功能清楚地表明囊泡 Gal9 在 mregDC 诱导中的重要作用。这些结果首次揭示了NPCSEV利用半乳糖凝集素9依赖性机制促进mregDC的出现，并为针对NPCSEV的抗肿瘤免疫治疗开辟了新的前景。