Small extracellular vesicles (sEV, or exosomes) communication among cells in the tumor microenvironment has been modeled mainly in cell culture, while their relevance in cancer pathogenesis and progression in vivo is less characterized. Here we investigated cancer-microenvironment interactions in vivo using mouse models of chronic lymphocytic leukemia (CLL). sEV isolated directly from CLL tissue were enriched in specific miRNA and immune checkpoint ligands. Distinct molecular components of tumor-derived sEV altered CD8+ T-cell transcriptome, proteome and metabolome leading to decreased functions and cell exhaustion ex vivo and in vivo. Using antagomiRs and blocking antibodies, we defined specific cargo-mediated alterations on CD8+ T-cells. Abrogating sEV biogenesis by Rab27a/b knockout dramatically delayed CLL pathogenesis. This phenotype was rescued by exogenous leukemic sEV or CD8+ T-cell depletion. Finally, high expression of sEV-related genes correlated with poor outcomes in CLL patients, suggesting sEV profiling as prognostic tool. In conclusion, sEV shape the immune microenvironment during CLL progression.

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