Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses.
Journal
Blood cancer discovery
ISSN: 2643-3249
Titre abrégé: Blood Cancer Discov
Pays: United States
ID NLM: 101764786
Informations de publication
Date de publication:
06 01 2023
06 01 2023
Historique:
received:
24
02
2022
revised:
04
07
2022
accepted:
07
09
2022
pubmed:
16
9
2022
medline:
10
1
2023
entrez:
15
9
2022
Statut:
ppublish
Résumé
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. sEVs produced in the leukemia microenvironment impair CD8+ T-cell mediated antitumor immune response and are indispensable for leukemia progression in vivo in murine preclinical models. In addition, high expression of sEV-related genes correlated with poor survival and unfavorable clinical parameters in CLL patients. See related commentary by Zhong and Guo, p. 5. This article is highlighted in the In This Issue feature, p. 1.
Identifiants
pubmed: 36108149
pii: 712653
doi: 10.1158/2643-3230.BCD-22-0029
pmc: PMC9816815
doi:
Types de publication
Editorial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
54-77Subventions
Organisme : Fonds National de la Recherche Luxembourg (FNR)
ID : PRIDE15/10675146/CANBIO
Organisme : Fonds National de la Recherche Luxembourg (FNR)
ID : INTER/DFG/16/11509946
Organisme : Fonds National de la Recherche Luxembourg (FNR)
ID : C20/BM/14582635
Organisme : Fonds National de la Recherche Luxembourg (FNR)
ID : C20/BM/14592342
Organisme : Fonds National de la Recherche Luxembourg (FNR)
ID : A18/BM/11809970
Organisme : Fonds National de la Recherche Luxembourg (FNR)
ID : P16/BM/11192868
Organisme : European Commission (EC)
ID : H2020-MSCA-IF-2020: 101029602
Organisme : Fonds De La Recherche Scientifique - FNRS (FNRS)
ID : 7.4509.20
Organisme : Fonds De La Recherche Scientifique - FNRS (FNRS)
ID : 7.8506.19
Organisme : Fonds De La Recherche Scientifique - FNRS (FNRS)
ID : 7.4503.19
Organisme : Fonds De La Recherche Scientifique - FNRS (FNRS)
ID : 7.6604.21
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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