Research ArticleCancer

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

See allHide authors and affiliations

Science Translational Medicine  30 Sep 2020:
Vol. 12, Issue 563, eaaz3426
DOI: 10.1126/scitranslmed.aaz3426

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

No holds barred for antitumor attack

Epstein-Barr virus (EBV) is a common pathogen that contributes to the development of several cancers, which can be difficult to treat. γδ-T cells have innate activity and have been proposed as a cancer immunotherapy, but they have been difficult to apply, particularly because they have to be individually prepared for each patient. To overcome the hurdles associated with whole γδ-T cell–based therapy, Wang et al. isolated exosomes from a subtype of activated γδ-T cells, which contained multiple immunostimulatory molecules and cell death–inducing ligands. These exosomes were effective against multiple mouse models of EBV-associated cancers and did not require customized preparation unlike cell-based therapies.

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.

View Full Text

Stay Connected to Science Translational Medicine