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.
Author Info: (1) Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China. (2) Department of Pathology, Li Ka Shi
Author Info: (1) Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China. (2) Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China. (3) Biostatistics and Clinical Research Methodology Unit, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China. (4) Institute of Immunology, University of Science and Technology of China, Hefei, Anhui 230027, China. (5) Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China. wwtu@hku.hk.
