Novel antitumor therapeutic strategy using CD4+ T cell-derived extracellular vesicles

Extracellular vesicles (EVs) mediate cell-cell crosstalk by carrying bioactive molecules derived from cells. Recently, immune cell-derived EVs have been reported to regulate key biological functions such as tumor progression. CD4sup+/supT cells orchestrate overall immunity; however, the biological role of their EVs is unclear. This study reveals that EVs derived from CD4sup+/supT cells increase the antitumor response of CD8sup+/supT cells by enhancing their proliferation and activity without affecting regulatory T cells (Tregs). Moreover, EVs derived from interleukin-2 (IL2)-stimulated CD4sup+/supT cells induce a more enhanced antitumor response of CD8sup+/supT cells compared with that of IL2-unstimulated CD4sup+/supT cell-derived EVs. Mechanistically, miR-25-3p, miR-155-5p, miR-215-5p, and miR-375 within CD4sup+/supT cell-derived EVs are responsible for the induction of CD8sup+/supT cell-mediated antitumor responses. In a melanoma mouse model, the EVs potently suppress tumor growth through CD8sup+/supT cell activation. This study demonstrates that the EVs, in addition to IL2, are important mediators between CD4sup+/supand CD8sup+/supT cells. Furthermore, unlike IL2, clinically used as an antitumor agent, CD4sup+/supT cell-derived EVs stimulate CD8sup+/supT cells without activating Tregs. Therefore, CD4sup+/supT cell-derived EVs may provide a novel direction for cancer immunotherapy by inducing a CD8sup+/supT cell-mediated antitumor response.