Abstract Text: Nasopharyngeal carcinoma (NPC) is one of the most prevalent and aggressive tumors in Southeast Asia. Radiotherapy is the first-line treatment for NPC, but its therapeutic efficacy is poor in some patients due to radioresistance. Chronic inflammation in tumor microenvironment is thought to be associated with radioresistance. γδT-17 cells are important cellular source of inflammatory cytokine and associated with tumor progression. However, whether and how γδT-17 cells affect radiotherapy in NPC remains elusive. In this study, we identified abundant γδT-17 cells in NPC tissues. Exosomes-derived from NPC cells (NPC-Exos) could induce γδT-17 cells. NPC-Exos-induced γδT-17 cells could further promote NPC radioresistance both in vitro and in vivo. Blockage of IL-17 secreted from NPC-Exos-induced γδT-17 cells enhanced the radiosensitivity of NPC cells and increased radiation-induced cell death. Mechanistic study revealed that both IL-17-driving cytokines from DCs and down-regulated CD25/IL-2 signaling of γδ-T cells induced by NPC-Exos contributed to the induction of γδT-17 cells. Furthermore, down-regulated CD25/IL-2 signaling was mediated by the delivery of tumor exosomal miR-15a to γδ-T cells. miR-15a inhibitor could successfully suppress the induction of γδT-17 cells by NPC-Exos. Our study demonstrates a novel immunoregulatory effects of NPC-Exos and provides implications to overcome NPC radioresistance.
