Exosomes derived from Vδ2-T cells control Epstein-Barr virus-associated tumors and induce T cell antitumor immunity.

Treatment of life-threatening Epstein-Barr virus (EBV)-associated tumors remains a great challenge, especially for patients with relapsed or refractory disease. Here, we found that exosomes derived from phosphoantigen-expanded V delta 2-T cells (V delta 2-T-Exos) contained death-inducing ligands (FasL and TRAIL), an activating receptor for natural killer (NK) cells (NKG2D), immunostimulatory ligands (CD80 and CD86), and antigen-presenting molecules (MHC class I and II). V delta 2-T-Exos targeted and efficiently killed EBV-associated tumor cells through FasL and TRAIL pathways and promoted EBV antigen-specific CD4 and CD8 T cell expansion. Administration of V delta 2-T-Exos effectively controlled EBV-associated tumors in Rag2(-/-)gamma c(-/-) and humanized mice. Because expanding V delta 2-T cells and preparing autologous V delta 2-T-Exos from cancer patients ex vivo in large scale is challenging, we explored the antitumor activity of allogeneic V delta 2-T-Exos in humanized mouse cancer models. Here, we found that allogeneic V delta 2-T-Exos had more effective antitumor activity than autologous V delta 2-T-Exos in humanized mice; the allogeneic V delta 2-T-Exos increased the infiltration of T cells into tumor tissues and induced more robust CD4 and CD8 T cell-mediated antitumor immunity. Compared with exosomes derived from NK cells (NK-Exos) with direct cytotoxic antitumor activity or dendritic cells (DC-Exos) that induced T cell antitumor responses, V delta 2-T-Exos directly killed tumor cells and induced T cell-mediated antitumor response, thus resulting in more effective control of EBV-associated tumors. This study provided proof of concept for the strategy of using V delta 2-T-Exos, especially allogeneic V delta 2-T-Exos, to treat EBV-associated tumors.