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

Autores
Gargiulo, Ernesto; Viry, Elodie; Morande, Pablo Elías; Largeot, Anne; Gonder, Susanne; Xian, Feng; Ionnou, Nikolaos; Benzarti, Mohaned; Borgmann, Felix Kleine; Mittelbronn, Michel; Dittmar, Gunnar; Nazarov, Petr V.; Meiser, Johannes; Stamatopoulos, Basile; Ramsay, Alan G.
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Gargiulo, Ernesto. Luxembourg Institute Of Health; Luxemburgo
Fil: Viry, Elodie. Luxembourg Institute Of Health; Luxemburgo
Fil: Morande, Pablo Elías. Luxembourg Institute Of Health; Luxemburgo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Largeot, Anne. Luxembourg Institute Of Health; Luxemburgo
Fil: Gonder, Susanne. Luxembourg Institute Of Health; Luxemburgo
Fil: Xian, Feng. Luxembourg Institute Of Health; Luxemburgo
Fil: Ionnou, Nikolaos. Centre Hospitalier de Luxembourg; Luxemburgo
Fil: Benzarti, Mohaned. Luxembourg Institute Of Health; Luxemburgo
Fil: Borgmann, Felix Kleine. University of Luxembourg; Luxemburgo. Luxembourg Institute Of Health; Luxemburgo
Fil: Mittelbronn, Michel. University of Luxembourg; Luxemburgo
Fil: Dittmar, Gunnar. Luxembourg Institute Of Health; Luxemburgo
Fil: Nazarov, Petr V.. Luxembourg Institute Of Health; Luxemburgo
Fil: Meiser, Johannes. Luxembourg Institute Of Health; Luxemburgo
Fil: Stamatopoulos, Basile. Université Libre de Bruxelles; Bélgica
Fil: Ramsay, Alan G.. King's College London; Reino Unido
Materia
Small extracellular vesicle
Leukemia Cells
Antitumor T-cell Responses
Hamper
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/228059
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/228059
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell ResponsesGargiulo, ErnestoViry, ElodieMorande, Pablo ElíasLargeot, AnneGonder, SusanneXian, FengIonnou, NikolaosBenzarti, MohanedBorgmann, Felix KleineMittelbronn, MichelDittmar, GunnarNazarov, Petr V.Meiser, JohannesStamatopoulos, BasileRamsay, Alan G.Small extracellular vesicleLeukemia CellsAntitumor T-cell ResponsesHamperhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Small 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.Fil: Gargiulo, Ernesto. Luxembourg Institute Of Health; LuxemburgoFil: Viry, Elodie. Luxembourg Institute Of Health; LuxemburgoFil: Morande, Pablo Elías. Luxembourg Institute Of Health; Luxemburgo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Largeot, Anne. Luxembourg Institute Of Health; LuxemburgoFil: Gonder, Susanne. Luxembourg Institute Of Health; LuxemburgoFil: Xian, Feng. Luxembourg Institute Of Health; LuxemburgoFil: Ionnou, Nikolaos. Centre Hospitalier de Luxembourg; LuxemburgoFil: Benzarti, Mohaned. Luxembourg Institute Of Health; LuxemburgoFil: Borgmann, Felix Kleine. University of Luxembourg; Luxemburgo. Luxembourg Institute Of Health; LuxemburgoFil: Mittelbronn, Michel. University of Luxembourg; LuxemburgoFil: Dittmar, Gunnar. Luxembourg Institute Of Health; LuxemburgoFil: Nazarov, Petr V.. Luxembourg Institute Of Health; LuxemburgoFil: Meiser, Johannes. Luxembourg Institute Of Health; LuxemburgoFil: Stamatopoulos, Basile. Université Libre de Bruxelles; BélgicaFil: Ramsay, Alan G.. King's College London; Reino UnidoAmerican Association for Cancer Research Inc.2023-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/228059Gargiulo, Ernesto; Viry, Elodie; Morande, Pablo Elías; Largeot, Anne; Gonder, Susanne; et al.; Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses; American Association for Cancer Research Inc.; Blood Cancer Discovery; 4; 1; 1-2023; 54-772643-32302643-3249CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://aacrjournals.org/bloodcancerdiscov/article/4/1/54/712653/Extracellular-Vesicle-Secretion-by-Leukemia-Cellsinfo:eu-repo/semantics/altIdentifier/doi/10.1158/2643-3230.BCD-22-0029info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:21:43Zoai:ri.conicet.gov.ar:11336/228059instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:21:43.295CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses
title Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses
spellingShingle Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses
Gargiulo, Ernesto
Small extracellular vesicle
Leukemia Cells
Antitumor T-cell Responses
Hamper
title_short Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses
title_full Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses
title_fullStr Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses
title_full_unstemmed Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses
title_sort Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses
dc.creator.none.fl_str_mv Gargiulo, Ernesto
Viry, Elodie
Morande, Pablo Elías
Largeot, Anne
Gonder, Susanne
Xian, Feng
Ionnou, Nikolaos
Benzarti, Mohaned
Borgmann, Felix Kleine
Mittelbronn, Michel
Dittmar, Gunnar
Nazarov, Petr V.
Meiser, Johannes
Stamatopoulos, Basile
Ramsay, Alan G.
author Gargiulo, Ernesto
author_facet Gargiulo, Ernesto
Viry, Elodie
Morande, Pablo Elías
Largeot, Anne
Gonder, Susanne
Xian, Feng
Ionnou, Nikolaos
Benzarti, Mohaned
Borgmann, Felix Kleine
Mittelbronn, Michel
Dittmar, Gunnar
Nazarov, Petr V.
Meiser, Johannes
Stamatopoulos, Basile
Ramsay, Alan G.
author_role author
author2 Viry, Elodie
Morande, Pablo Elías
Largeot, Anne
Gonder, Susanne
Xian, Feng
Ionnou, Nikolaos
Benzarti, Mohaned
Borgmann, Felix Kleine
Mittelbronn, Michel
Dittmar, Gunnar
Nazarov, Petr V.
Meiser, Johannes
Stamatopoulos, Basile
Ramsay, Alan G.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Small extracellular vesicle
Leukemia Cells
Antitumor T-cell Responses
Hamper
topic Small extracellular vesicle
Leukemia Cells
Antitumor T-cell Responses
Hamper
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Gargiulo, Ernesto. Luxembourg Institute Of Health; Luxemburgo
Fil: Viry, Elodie. Luxembourg Institute Of Health; Luxemburgo
Fil: Morande, Pablo Elías. Luxembourg Institute Of Health; Luxemburgo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Largeot, Anne. Luxembourg Institute Of Health; Luxemburgo
Fil: Gonder, Susanne. Luxembourg Institute Of Health; Luxemburgo
Fil: Xian, Feng. Luxembourg Institute Of Health; Luxemburgo
Fil: Ionnou, Nikolaos. Centre Hospitalier de Luxembourg; Luxemburgo
Fil: Benzarti, Mohaned. Luxembourg Institute Of Health; Luxemburgo
Fil: Borgmann, Felix Kleine. University of Luxembourg; Luxemburgo. Luxembourg Institute Of Health; Luxemburgo
Fil: Mittelbronn, Michel. University of Luxembourg; Luxemburgo
Fil: Dittmar, Gunnar. Luxembourg Institute Of Health; Luxemburgo
Fil: Nazarov, Petr V.. Luxembourg Institute Of Health; Luxemburgo
Fil: Meiser, Johannes. Luxembourg Institute Of Health; Luxemburgo
Fil: Stamatopoulos, Basile. Université Libre de Bruxelles; Bélgica
Fil: Ramsay, Alan G.. King's College London; Reino Unido
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/228059
Gargiulo, Ernesto; Viry, Elodie; Morande, Pablo Elías; Largeot, Anne; Gonder, Susanne; et al.; Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses; American Association for Cancer Research Inc.; Blood Cancer Discovery; 4; 1; 1-2023; 54-77
2643-3230
2643-3249
CONICET Digital
CONICET
url http://hdl.handle.net/11336/228059
identifier_str_mv Gargiulo, Ernesto; Viry, Elodie; Morande, Pablo Elías; Largeot, Anne; Gonder, Susanne; et al.; Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses; American Association for Cancer Research Inc.; Blood Cancer Discovery; 4; 1; 1-2023; 54-77
2643-3230
2643-3249
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://aacrjournals.org/bloodcancerdiscov/article/4/1/54/712653/Extracellular-Vesicle-Secretion-by-Leukemia-Cells
info:eu-repo/semantics/altIdentifier/doi/10.1158/2643-3230.BCD-22-0029
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research Inc.
publisher.none.fl_str_mv American Association for Cancer Research Inc.
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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