Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses

Ernesto Gargiulo, Elodie Viry, Pablo Elías Morande, Anne Largeot, Susanne Gonder, Feng Xian, Nikolaos Ioannou, Mohaned Benzarti, Felix Bruno Kleine Borgmann, Michel Mittelbronn, Gunnar Dittmar, Petr V. Nazarov, Johannes Meiser, Basile Stamatopoulos, Alan G. Ramsay, Etienne Moussay* (Main author), Jérôme Paggetti*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

Small extracellular vesicle (sEV, or exosome) communication among cells in the tumor microenvironment has been modeled mainly in cell culture, whereas 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). sEVs isolated directly from CLL tissue were enriched in specific miRNA and immune-checkpoint ligands. Distinct molecular components of tumor-derived sEVs 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 a prognostic tool. In conclusion, sEVs shape the immune microenvironment during CLL progression.

Original languageEnglish
Pages (from-to)54-77
Number of pages24
JournalBlood Cancer Discovery
Volume4
Issue number1
Early online date15 Sept 2022
DOIs
Publication statusPublished - 6 Jan 2023

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