%0 Journal Article
%T Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral ¦Ã¦Ä T cell equilibrium via tumor-derived exosomes
%J -
%D 2018
%R https://doi.org/10.1038/s41388-018-0627-z
%X ¦Ã¦Ä T cells are a unique lymphocyte population that have been reported to have either anti- or pro-tumoral functions in several cancer types, but the mechanisms are underinvestigated. Exosomes, initially considered to be cellular ¡°garbage dumpsters,¡± are now implicated in mediating interactions with the cellular environment. Hypoxia is a common feature of solid tumors and is believed to alter tumor-derived exosomes (TEXs), which mediate the hypoxic evolution of the tumor microenvironment in return. This study sought to investigate whether TEXs mediate the anti- and pro-tumoral equilibrium of ¦Ã¦Ä T cells under different oxygen pressures in the tumor microenvironment. We show that TEXs can alter the expansion and cytotoxicity of ¦Ã¦Ä T cells in an HSP70-dependent but dendritic cell-independent manner. The stimulating effects of normoxic TEXs on ¦Ã¦Ä T-cell activity were absent from hypoxic TEXs, which enhanced the suppressive effect of myeloid-derived suppressor cells (MDSCs) on ¦Ã¦Ä T cells through a miR-21/PTEN/PD-L1 regulation axis. Finally, the therapeutic outcome benefited from combined miR-21 and PD-L1 targeting in oral squamous cell carcinoma (OSCC)-bearing immunocompetent mice. We conclude that oxygen pressure in the tumor microenvironment orchestrates an anti- and pro-tumoral ¦Ã¦Ä T-cell equilibrium by altering TEX content, which subsequently regulates MDSC function in a miR-21/PTEN/PD-L1-axis-dependent manner. Our results should prompt further investigation into integrated exosomal miRNA inhibition and immune checkpoint inhibitor therapeutic modalities for patients with OSCC
%U https://www.nature.com/articles/s41388-018-0627-z