Exosomes derived from human Vγ9Vδ2-T cells exert therapeutic effects on Epstein-Barr virus-induced B cell lymphoproliferative disease.

Abstract

Exosomes are nanovesicles of endosomal origin and carry bioactive macromolecules to mediate intercellular communication. Some hematopoietic cells derived exosomes have been demonstrated to regulate tumorigenesis. However, the characteristics and functions of exosomes derived from human Vγ9Vδ2-T cells (Vγ9Vδ2-T-Exos) remain unclear. Previously we have demonstrated that Vγ9Vδ2-T cells can be largely expanded in vitro and control Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD). However, this therapeutic effect could be counteracted by the immunosuppressive factors and acidity in tumor microenvironment. On the contrary, exosomes are resistant to immunosuppression and their accumulation and delivery can be enhanced by tumor acidity. As cell-free bioactive vesicles with good feasibility and safety, exosomes attract more and more attention in the field of cancer immunotherapy. In this study, we characterized Vγ9Vδ2-T-Exos and explored their anti-tumor effects against EBV-LPD. The Vγ9Vδ2-T-Exos were isolated by differential ultracentrifugation and identified with typical cup-shaped morphology, expression of exosomal markers CD63 and CD81. Vγ9Vδ2-T-Exos were found to carry killer proteins and display significant cytotoxic activity against EBV-transformed lymphoblastoid B cell lines (EBV-LCL) in vitro, which was partially through the expression of FasL and TRAIL. Lethal EBV-LPD tumor model was established by subcutaneous inoculation of EBV-LCL in Rag2-/-γc-/- mice. Administration of Vγ9Vδ2-TExos significantly decreased the tumor incidences and inhibited tumor growth of EBV-LPD in Rag2-/-γc-/- mice. Moreover, the survival of EBV-LPD-bearing Rag2-/-γc-/- mice were significantly enhanced after the treatment with Vγ9Vδ2-T-Exos. This study firstly demonstrated that Vγ9Vδ2-T-Exos could exert anti-tumor effects and thus warrant further development as a potential immunotherapeutic strategy against cancer.