Exosomes derived from 3δ -T cells synergize with radiotherapy and preserve antitumor activities against nasopharyngeal carcinoma in immunosuppressive microenvironment

Abstract

Background Radiotherapy is the first-line treatment for patients nasopharyngeal carcinoma (NPC), but its therapeutic efficacy is poor in some patients due to radioresistance. Adoptive T cell-based immunotherapy has also shown promise to control NPC; however, its antitumor efficacy may be attenuated by an immunosuppressive tumor microenvironment. Exosomes derived from 3δ -T cells ( 3δ -T-Exos) have potent antitumor potentials. However, it remains unknown whether 3δ -T-Exos have synergistic effect with radiotherapy and preserve their antitumor activities against NPC in an immunosuppressive tumor microenvironment. Methods 3δ -T-Exos were stained with fluorescent membrane dye, and their interactions with NPC were determined both in vitro and in vivo. NPC cell deaths were detected after treatment with 3δ -T-Exos and/or irradiation. Moreover, effects of 3δ -T-Exos on radioresistant cancer stem-like cells (CSCs) were determined. The therapeutic efficacy of combination therapy using 3δ -T-Exos and irradiation on NPC tumor progression was also monitored in vivo. Finally, the tumor-killing and T cell-promoting activities of 3δ -T-Exos were determined under the culture in immunosuppressive NPC supernatant. Results 3δ -T-Exos effectively interacted with NPC tumor cells in vitro and in vivo. 3δ -T-Exos not only killed NPC cells in vitro, which was mainly mediated by Fas/Fas ligand (FasL) and death receptor 5 (DR5)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways, but also controlled NPC tumor growth and prolonged tumor-bearing mice survival in vivo. Furthermore, 3δ -T-Exos selectively targeted the radioresistant CD44 +/high CSCs and induced profound cell apoptosis. The combination of 3δ -T-Exos with radiotherapy overcame the radioresistance of CD44 +/high NPC cells and significantly improved its therapeutic efficacy against NPC in vitro and in vivo. In addition, 3δ -T-Exos promoted T-cell migration into NPC tumors by upregulating CCR5 on T cells that were chemoattracted by CCR5 ligands in the NPC tumor microenvironment. Although NPC tumor cells secreted abundant tumor growth factor beta to suppress T-cell responses, 3δ -T-Exos preserved their direct antitumor activities and overcame the immunosuppressive NPC microenvironment to amplify T-cell antitumor immunity. Conclusions 3δ -T-Exos synergized with radiotherapy to control NPC by overcoming the radioresistance of NPC CSCs. Moreover, 3δ -T-Exos preserved their tumor-killing and T cell-promoting activities in the immunosuppressive NPC microenvironment. This study provides a proof of concept for a novel and potent strategy by combining 3δ -T-Exos with radiotherapy in the control of NPC.