CD25 downregulation by tumor exosomal microRNA‐15a promotes interleukin‐17‐producing γδ‐T‐cells‐mediated radioresistance in nasopharyngeal carcinoma

Interleukin (IL)-17-producing γδ-T cells (γδT-17) are a major source of IL-17 within the tumor microenvironment and have been shown to influence tumor development and therapy outcomes in various cancers. However, the role and presence of γδT-17 cells in nasopharyngeal carcinoma (NPC) remain poorly understood. It is also unclear how these cells might affect radiotherapy, the primary treatment for NPC patients. In this study, we discovered that NPC tumor tissues were rich in γδT-17 cells. Exosomes released from NPC cells (NPC-Exos) could direct γδ-T cells to differentiate into γδT-17 cells. These NPC-Exos-induced γδT-17 cells were found to enhance radioresistance in NPC, both in vitro and in vivo. Blocking IL-17 secreted by NPC-Exos-induced γδT-17 cells restored NPC cell sensitivity to radiation and elevated radiation-induced cell death. Mechanistic studies revealed that NPC-Exos not only increased the release of IL-17-promoting cytokines IL-1β, IL-6, and IL-23 from dendritic cells, but also suppressed CD25/IL-2 signaling in γδ-T cells, facilitating γδT-17 differentiation. The suppression of CD25/IL-2 signaling was driven by microRNA-15a (miR-15a) carried by NPC exosomes. Furthermore, miR-15a inhibitors were able to prevent γδT-17 induction by NPC-Exos. Our findings reveal a novel immunoregulatory role of NPC-Exos and offer potential strategies to combat NPC radioresistance.