TY - JOUR
T1 - Extracellular vesicle secretion by leukemia cells in vivo promotes CLL progression by hampering antitumor T-cell responses
AU - Gargiulo, Ernesto
AU - Viry, Elodie
AU - Morande, Pablo Elias
AU - Largeot, Anne
AU - Gonder, Susanne
AU - Xian, Feng
AU - Ioannou, Nikolaos
AU - Benzarti, Mohaned
AU - Kleine Borgmann, Felix Bruno
AU - Mittelbronn, Michel
AU - Dittmar, Gunnar
AU - Nazarov, Petr V
AU - Meiser, Johannes
AU - Stamatopoulos, Basile
AU - Ramsay, Alan G
AU - Moussay, Etienne
AU - Paggetti, Jerome
N1 - Funding: This work was supported by grants from the Luxembourg National Research Fund (FNR) to EG, EM and JP (PRIDE15/10675146/CANBIO, INTER/DFG/16/11509946, C20/BM/14582635, and C20/BM/14592342), to JM (ATTRACT grant A18/BM/11809970), and to MM (PEARL grant P16/BM/11192868), from FNRS-Télévie to EV, PEM, AL, and SG (7.4509.20, 7.8506.19, 7.4503.19, and 7.6604.21), from the European commission to PEM (H2020-MSCA-IF-2020: 101029602).
PY - 2023/1/6
Y1 - 2023/1/6
N2 - 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.
AB - 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.
UR - https://pubmed.ncbi.nlm.nih.gov/36108149
U2 - 10.1158/2643-3230.BCD-22-0029
DO - 10.1158/2643-3230.BCD-22-0029
M3 - Article
C2 - 36108149
SN - 2643-3230
VL - 4
SP - 54
EP - 77
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 1
ER -