Wang et al. demonstrated that Vδ2-T cell-derived exosomes (Vδ2-T-Exos) induced EBV tumor cell apoptosis and activated CD4+ and CD8+ T cell–mediated antitumor immunity. Vδ2-T-Exos contained death-inducing ligands FasL and TRAIL, NKG2D, MHC class I and II, CD80, and CD86. Vδ2-T-Exos required NKG2D to enter EBV tumor cells, and FasL and TRAIL ligands to induce apoptosis. Vδ2-T-Exos controlled EBV-associated tumors in Rag2−/−γc−/− and humanized mice. Allogeneic Vδ2-T-Exos enhanced T cell recruitment, activation, and expansion, and demonstrated superior EBV tumor control over autologous Vδ2-T-Exos, DC-Exos, and NK-Exos.
Contributed by Shishir Pant
ABSTRACT: 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 Vδ2-T cells (Vδ2-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). Vδ2-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 Vδ2-T-Exos effectively controlled EBV-associated tumors in Rag2-/-γc-/- and humanized mice. Because expanding Vδ2-T cells and preparing autologous Vδ2-T-Exos from cancer patients ex vivo in large scale is challenging, we explored the antitumor activity of allogeneic Vδ2-T-Exos in humanized mouse cancer models. Here, we found that allogeneic Vδ2-T-Exos had more effective antitumor activity than autologous Vδ2-T-Exos in humanized mice; the allogeneic Vδ2-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, Vδ2-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 Vδ2-T-Exos, especially allogeneic Vδ2-T-Exos, to treat EBV-associated tumors.