In this study, we sought to investigate the potential application of γδ T cell-derived extracellular vesicles (γδTDEs) as drug delivery system (DDS) for miR-138 in the treatment of oral squamous cell carcinoma (OSCC). Our data showed that overexpression of miR-138 in γδ T cells obtained miR-138-rich γδTDEs accompanying increased expansion and cytotoxicity of γδ T cells. γδTDEs inherited the cytotoxic profile of γδ T cells and could efficiently deliver miR-138 to OSCC cells, resulting in synergetic inhibition on OSCC both in vitro and in vivo. The pre-immunization by miR-138-rich γδTDEs inhibited the growth of OSCC tumors in immunocompetent C3H mice, but not in nude mice, suggesting an immunomodulatory role by miR-13-rich γδTDEs. γδTDEs and miR-138 additively increased the proliferation, interferon-γ (IFN-γ) production, and cytotoxicity of CD8⁺ T cells against OSCC cells. Only delivered by γδTDEs can miR-138 efficiently target programmed cell death 1 (PD-1) and CTLA-4 in CD8⁺ T cells. We conclude that γδTDEs delivering miR-138 could achieve synergetic therapeutic effects on OSCC, which is benefited from the individual direct anti-tumoral effects on OSCC and immunostimulatory effects on T cells by both γδTDEs and miR-138; γδTDEs could serve as an efficient DDS for microRNAs (miRNAs) in the treatment of cancer.

在这项研究中，我们寻求研究源自γδT细胞的细胞外囊泡（γδTDEs）作为miR-138的药物递送系统（DDS）在治疗口腔鳞状细胞癌（OSCC）中的潜在应用。我们的数据表明，在γδT细胞中过表达miR-138获得了富含miR-138的γδTDE，伴随着γδT细胞的扩增和细胞毒性增加。γδTDEs继承γδT细胞的细胞毒轮廓和可有效地提供的miR-138 OSCC细胞，导致两者上OSCC协同抑制在体外和体内。富含miR-138的γδTDEs的预免疫抑制了具有免疫能力的C3H小鼠中OSCC肿瘤的生长，但没有抑制裸鼠，这表明富含miR-13的γδTDEs具有免疫调节作用。γδTDE和miR-138可增加CD8 ⁺ T细胞对OSCC细胞的增殖，干扰素-γ（IFN-γ）的产生和细胞毒性。只有通过γδTDE传递的miR-138才能有效靶向CD8 ⁺ T细胞中的程序性细胞死亡1（PD-1）和CTLA-4 。我们得出的结论是，传递miR-138的γδTDEs可以对OSCC发挥协同治疗作用，这得益于γδTDEs和miR-138对OSCC的直接直接抗肿瘤作用以及对T细胞的免疫刺激作用。γδTDEs可以作为microRNA（miRNA）在癌症治疗中的有效DDS。