Roles of Vδ2+-T cells derived exosomes in the control of Epstein-Barr virus-induced B-cell lymphoma

Abstract

Human Vδ2+-T cells have a broad antitumor spectrum. However, their therapeutic effect could be counteracted by the immunosuppressive factors in tumor microenvironment. Safety is also a concern of Vδ2+-T-cell-based immunotherapy in clinical application, because more and more studies found that tumor microenvironment might polarize Vδ2+-T cells into a protumor phenotype. As bioactive extracellular vesicles with good feasibility, safety, and resistance to immunosuppression tumor microenvironment, exosomes have attracted more and more research interest in the field of cancer immunotherapy. However, it remains unclear about the characteristics and antitumor activities of exosomes derived from Vδ2+-T cells (Vδ2-T-Exos). As one of the common life-threatening malignances, treatment of EBV-induced B-cell lymphoma remains a great challenge, especially for relapsed or refractory diseases. Here, we found that Vδ2-T-Exos carried high levels of cytolytic (FasL and TRAIL), activating (NKG2D), immunostimulatory (CD80 and CD86), and MHC class I/II molecules. Vδ2-T-Exos had NKG2D-dependent targeting ability toward EBV-induced B-cell lymphoma. Vδ2-T-Exos also efficiently killed EBV-transformed lymphoblastoid B cell lines (EBV-LCL) through FasL and TRAIL pathways, and promote EBV antigen-specific CD4 and CD8 T cell expansion. Furthermore, administration of Vδ2-T-Exos effectively inhibited the growth of EBV-induced B-cell lymphoma in Rag2-/-γc-/- and humanized mice. As most cancer patients are immunocompromised, it is difficult to expand their Vδ2+-T cells and prepare autologous Vδ2-T-Exos ex vivo in large scale. In addition, the compositions of Vδ2-T-Exos from each patient are also different. In contrast, it is convenient to expand and prepare allogeneic Vδ2-T-Exos ex vivo in large scale from healthy individuals by currently available protocols. Given phosphoantigens-expanded Vδ2+-T cells display a homogeneous antitumor Th1 phenotype, therefore, pooling allogeneic Vδ2-T-Exos together from a large number of healthy individuals will be beneficial to quality control, standardization and centralization. Notably, allogeneic Vδ2-T-Exos had more potent antitumor activity than autologous Vδ2-T-Exos in humanized mice because they could induce more robust CD4 and CD8 T cells-medicated antitumor immunity. As cell-free exosomes are more resistant to tumor immunosuppressive microenvironment, this study provides proof-of-concept for a novel and potent strategy by using Vδ2-T-Exos, especially allogeneic Vδ2-T-Exos, to treat EBV-induced B-cell lymphoma, and thus warrant further development as a potential immunotherapeutic strategy against EBV-induced B-cell lymphoma.