CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells

Autores
Canale, Fernando Pablo; Ramello, María Cecilia; Nuñez, Nicolás; Araujo Furlan, Cintia Liliana; Bossio, Sabrina Noemí; Gorosito Serran, Melisa; Tosello Boari, Jimena; del Castillo, Andrés; Ledesma, Marta; Sedlik, Christine; Piaggio, Eliane; Gruppi, Adriana; Acosta Rodriguez, Eva Virginia; Montes, Carolina Lucia
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ectonucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNg production by responderCD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within noninvaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNg, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induceCD39 on human CD8+ T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule onCD8+ T cells, withimplications for defining abiomarker of T-cell dysfunction and a target for immunotherapeutic intervention. Significance: The tumor microenvironment elicits a subset of functionally exhausted CD8+ T cells by creating conditions that induce cell surface expression of CD39, an immunosuppressive molecule that can be therapeutically targeted to restore effector T-cell function.
Fil: Canale, Fernando Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Ramello, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Nuñez, Nicolás. Institute Curie. U-932 Immunity And Cancer; Francia
Fil: Araujo Furlan, Cintia Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Bossio, Sabrina Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Gorosito Serran, Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: del Castillo, Andrés. Hospital Rawson; Argentina
Fil: Ledesma, Marta. Hospital Rawson; Argentina
Fil: Sedlik, Christine. Institute Curie. U-932 Immunity And Cancer; Francia
Fil: Piaggio, Eliane. Institute Curie. U-932 Immunity And Cancer; Francia
Fil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Materia
CD39
CD8 T CELL
EXHAUSTION
CANCER
IMMUNOREGULATION
Nivel de accesibilidad
acceso embargado
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:11336/50228
Acceder
id CONICETDig_cd805118ec9b84184631dfd598732412
oai_identifier_str oai:ri.conicet.gov.ar:11336/50228
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cellsCanale, Fernando PabloRamello, María CeciliaNuñez, NicolásAraujo Furlan, Cintia LilianaBossio, Sabrina NoemíGorosito Serran, MelisaTosello Boari, Jimenadel Castillo, AndrésLedesma, MartaSedlik, ChristinePiaggio, ElianeGruppi, AdrianaAcosta Rodriguez, Eva VirginiaMontes, Carolina LuciaCD39CD8 T CELLEXHAUSTIONCANCERIMMUNOREGULATIONhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ectonucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNg production by responderCD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within noninvaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNg, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induceCD39 on human CD8+ T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule onCD8+ T cells, withimplications for defining abiomarker of T-cell dysfunction and a target for immunotherapeutic intervention. Significance: The tumor microenvironment elicits a subset of functionally exhausted CD8+ T cells by creating conditions that induce cell surface expression of CD39, an immunosuppressive molecule that can be therapeutically targeted to restore effector T-cell function.Fil: Canale, Fernando Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Ramello, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Nuñez, Nicolás. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Araujo Furlan, Cintia Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Bossio, Sabrina Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gorosito Serran, Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: del Castillo, Andrés. Hospital Rawson; ArgentinaFil: Ledesma, Marta. Hospital Rawson; ArgentinaFil: Sedlik, Christine. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Piaggio, Eliane. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaAmerican Association for Cancer Research2018-01-24info:eu-repo/date/embargoEnd/2018-08-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/50228Canale, Fernando Pablo; Ramello, María Cecilia; Nuñez, Nicolás; Araujo Furlan, Cintia Liliana; Bossio, Sabrina Noemí; et al.; CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells; American Association for Cancer Research; Cancer Research; 78; 1; 24-1-2018; 115-1280008-54721538-7445CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-16-2684info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-16-2684info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/content/78/1/115info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pubmed/29066514info:eu-repo/semantics/embargoedAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:46:46Zoai:ri.conicet.gov.ar:11336/50228instacron: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:34982025-09-03 09:46:46.542CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells
title CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells
spellingShingle CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells
Canale, Fernando Pablo
CD39
CD8 T CELL
EXHAUSTION
CANCER
IMMUNOREGULATION
title_short CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells
title_full CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells
title_fullStr CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells
title_full_unstemmed CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells
title_sort CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells
dc.creator.none.fl_str_mv Canale, Fernando Pablo
Ramello, María Cecilia
Nuñez, Nicolás
Araujo Furlan, Cintia Liliana
Bossio, Sabrina Noemí
Gorosito Serran, Melisa
Tosello Boari, Jimena
del Castillo, Andrés
Ledesma, Marta
Sedlik, Christine
Piaggio, Eliane
Gruppi, Adriana
Acosta Rodriguez, Eva Virginia
Montes, Carolina Lucia
author Canale, Fernando Pablo
author_facet Canale, Fernando Pablo
Ramello, María Cecilia
Nuñez, Nicolás
Araujo Furlan, Cintia Liliana
Bossio, Sabrina Noemí
Gorosito Serran, Melisa
Tosello Boari, Jimena
del Castillo, Andrés
Ledesma, Marta
Sedlik, Christine
Piaggio, Eliane
Gruppi, Adriana
Acosta Rodriguez, Eva Virginia
Montes, Carolina Lucia
author_role author
author2 Ramello, María Cecilia
Nuñez, Nicolás
Araujo Furlan, Cintia Liliana
Bossio, Sabrina Noemí
Gorosito Serran, Melisa
Tosello Boari, Jimena
del Castillo, Andrés
Ledesma, Marta
Sedlik, Christine
Piaggio, Eliane
Gruppi, Adriana
Acosta Rodriguez, Eva Virginia
Montes, Carolina Lucia
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CD39
CD8 T CELL
EXHAUSTION
CANCER
IMMUNOREGULATION
topic CD39
CD8 T CELL
EXHAUSTION
CANCER
IMMUNOREGULATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ectonucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNg production by responderCD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within noninvaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNg, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induceCD39 on human CD8+ T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule onCD8+ T cells, withimplications for defining abiomarker of T-cell dysfunction and a target for immunotherapeutic intervention. Significance: The tumor microenvironment elicits a subset of functionally exhausted CD8+ T cells by creating conditions that induce cell surface expression of CD39, an immunosuppressive molecule that can be therapeutically targeted to restore effector T-cell function.
Fil: Canale, Fernando Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Ramello, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Nuñez, Nicolás. Institute Curie. U-932 Immunity And Cancer; Francia
Fil: Araujo Furlan, Cintia Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Bossio, Sabrina Noemí. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Gorosito Serran, Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: del Castillo, Andrés. Hospital Rawson; Argentina
Fil: Ledesma, Marta. Hospital Rawson; Argentina
Fil: Sedlik, Christine. Institute Curie. U-932 Immunity And Cancer; Francia
Fil: Piaggio, Eliane. Institute Curie. U-932 Immunity And Cancer; Francia
Fil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
description The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ectonucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNg production by responderCD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within noninvaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNg, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induceCD39 on human CD8+ T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule onCD8+ T cells, withimplications for defining abiomarker of T-cell dysfunction and a target for immunotherapeutic intervention. Significance: The tumor microenvironment elicits a subset of functionally exhausted CD8+ T cells by creating conditions that induce cell surface expression of CD39, an immunosuppressive molecule that can be therapeutically targeted to restore effector T-cell function.
publishDate 2018
dc.date.none.fl_str_mv 2018-01-24
info:eu-repo/date/embargoEnd/2018-08-01
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/11336/50228
Canale, Fernando Pablo; Ramello, María Cecilia; Nuñez, Nicolás; Araujo Furlan, Cintia Liliana; Bossio, Sabrina Noemí; et al.; CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells; American Association for Cancer Research; Cancer Research; 78; 1; 24-1-2018; 115-128
0008-5472
1538-7445
CONICET Digital
CONICET
url http://hdl.handle.net/11336/50228
identifier_str_mv Canale, Fernando Pablo; Ramello, María Cecilia; Nuñez, Nicolás; Araujo Furlan, Cintia Liliana; Bossio, Sabrina Noemí; et al.; CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells; American Association for Cancer Research; Cancer Research; 78; 1; 24-1-2018; 115-128
0008-5472
1538-7445
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-16-2684
info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-16-2684
info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/content/78/1/115
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pubmed/29066514
dc.rights.none.fl_str_mv info:eu-repo/semantics/embargoedAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv embargoedAccess
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
publisher.none.fl_str_mv American Association for Cancer Research
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 13.13397

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