γδTDEs: An Efficient Delivery System for miR-138 with Anti-tumoral and Immunostimulatory Roles on Oral Squamous Cell Carcinoma

In this study, we sought to investigate the potential application of gamma delta T cell-derived extracellular vesicles (gamma delta TDEs) 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 gamma delta T cells obtained miR-138-rich gamma delta TDEs accompanying increased expansion and cytotoxicity of gamma delta T cells. gamma delta TDEs inherited the cytotoxic profile of gamma delta 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 gamma delta TDEs inhibited the growth of OSCC tumors in immunocompetent C3H mice, but not in nude mice, suggesting an immunomodulatory role by miR-13-rich gamma delta TDEs. gamma delta TDEs and miR-138 additively increased the proliferation, interferon-gamma (IFN-gamma) production, and cytotoxicity of CD8(+) T cells against OSCC cells. Only delivered by gamma delta TDEs can miR-138 efficiently target programmed cell death 1 (PD-1) and CTLA-4 in CD8(+) T cells. We conclude that gamma delta TDEs 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 gamma delta TDEs and miR-138; gamma delta TDEs could serve as an efficient DDS for microRNAs (miRNAs) in the treatment of cancer.