Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity

Autores
Fuertes, Mercedes Beatriz; Girart, Maria Victoria; Molinero, Luciana Lorena; Domaica, Carolina Ines; Rossi, Lucas Ezequiel; Barrio, Maria Marcela; Mordoh, Jose; Rabinovich, Gabriel Adrián; Zwirner, Norberto Walter
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Most tumors grow in immunocompetent hosts despite expressing NKG2D ligands (NKG2DLs) such as the MHC class I chain-related genes A and B (MICA/B). However, their participation in tumor cell evasion is still not completely understood. Here we demonstrate that several human melanomas (cell lines and freshly isolated metastases) do not express MICA on the cell surface but have intracellular deposits of this NKG2DL. Susceptibility to NK cell-mediated cytotoxicity correlated with the ratio of NKG2DLs to HLA class I molecules but not with the amounts of MICA on the cell surface of tumor cells. Transfection-mediated overexpression of MICA restored cell surface expression and resulted in an increased in vitro cytotoxicity and IFN-gamma secretion by human NK cells. In xenografted nude mice, these melanomas exhibited a delayed growth and extensive in vivo apoptosis. Retardation of tumor growth was due to NK cell-mediated antitumor activity against MICA-transfected tumors, given that this effect was not observed in NK cell-depleted mice. Also, mouse NK cells killed MICA-overexpressing melanomas in vitro. A mechanistic analysis revealed the retention of MICA in the endoplasmic reticulum, an effect that was associated with accumulation of endoH-sensitive (immature) forms of MICA, retrograde transport to the cytoplasm, and degradation by the proteasome. Our study identifies a novel strategy developed by melanoma cells to evade NK cell-mediated immune surveillance based on the intracellular sequestration of immature forms of MICA in the endoplasmic reticulum. Furthermore, this tumor immune escape strategy can be overcome by gene therapy approaches aimed at overexpressing MICA on tumor cells,
Fil: Fuertes, Mercedes Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Girart, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Molinero, Luciana Lorena. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina
Fil: Domaica, Carolina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Rossi, Lucas Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Barrio, Maria Marcela. Fundación P/la Invest.y Prevención del Cancer. Centro de Investigaciones Oncologicas; Argentina
Fil: Mordoh, Jose. Fundación Instituto Leloir; Argentina. Fundación P/la Invest.y Prevención del Cancer. Centro de Investigaciones Oncologicas; Argentina
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Zwirner, Norberto Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Materia
Melanoma
Nk Cells
Cancer
Cell Line Tumor
Mica
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:11336/25922
Acceder
id CONICETDig_6110771c41690406bc46e8c1076bb6a7
oai_identifier_str oai:ri.conicet.gov.ar:11336/25922
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicityFuertes, Mercedes BeatrizGirart, Maria VictoriaMolinero, Luciana LorenaDomaica, Carolina InesRossi, Lucas EzequielBarrio, Maria MarcelaMordoh, JoseRabinovich, Gabriel AdriánZwirner, Norberto WalterMelanomaNk CellsCancerCell Line TumorMicahttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Most tumors grow in immunocompetent hosts despite expressing NKG2D ligands (NKG2DLs) such as the MHC class I chain-related genes A and B (MICA/B). However, their participation in tumor cell evasion is still not completely understood. Here we demonstrate that several human melanomas (cell lines and freshly isolated metastases) do not express MICA on the cell surface but have intracellular deposits of this NKG2DL. Susceptibility to NK cell-mediated cytotoxicity correlated with the ratio of NKG2DLs to HLA class I molecules but not with the amounts of MICA on the cell surface of tumor cells. Transfection-mediated overexpression of MICA restored cell surface expression and resulted in an increased in vitro cytotoxicity and IFN-gamma secretion by human NK cells. In xenografted nude mice, these melanomas exhibited a delayed growth and extensive in vivo apoptosis. Retardation of tumor growth was due to NK cell-mediated antitumor activity against MICA-transfected tumors, given that this effect was not observed in NK cell-depleted mice. Also, mouse NK cells killed MICA-overexpressing melanomas in vitro. A mechanistic analysis revealed the retention of MICA in the endoplasmic reticulum, an effect that was associated with accumulation of endoH-sensitive (immature) forms of MICA, retrograde transport to the cytoplasm, and degradation by the proteasome. Our study identifies a novel strategy developed by melanoma cells to evade NK cell-mediated immune surveillance based on the intracellular sequestration of immature forms of MICA in the endoplasmic reticulum. Furthermore, this tumor immune escape strategy can be overcome by gene therapy approaches aimed at overexpressing MICA on tumor cells,Fil: Fuertes, Mercedes Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Girart, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Molinero, Luciana Lorena. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; ArgentinaFil: Domaica, Carolina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Rossi, Lucas Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Barrio, Maria Marcela. Fundación P/la Invest.y Prevención del Cancer. Centro de Investigaciones Oncologicas; ArgentinaFil: Mordoh, Jose. Fundación Instituto Leloir; Argentina. Fundación P/la Invest.y Prevención del Cancer. Centro de Investigaciones Oncologicas; ArgentinaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Zwirner, Norberto Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaAmerican Association of Immunologists2008info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/25922Fuertes, Mercedes Beatriz; Girart, Maria Victoria; Molinero, Luciana Lorena; Domaica, Carolina Ines; Rossi, Lucas Ezequiel; et al.; Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity; American Association of Immunologists; Journal of Immunology; 180; 7; 2008; 4606-46140022-17671550-6606CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jimmunol.org/content/180/7/4606info:eu-repo/semantics/altIdentifier/doi/10.4049/jimmunol.180.7.4606info:eu-repo/semantics/altIdentifier/pmid/18354183info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:38:56Zoai:ri.conicet.gov.ar:11336/25922instacron: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:34982025-10-15 14:38:56.83CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity
title Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity
spellingShingle Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity
Fuertes, Mercedes Beatriz
Melanoma
Nk Cells
Cancer
Cell Line Tumor
Mica
title_short Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity
title_full Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity
title_fullStr Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity
title_full_unstemmed Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity
title_sort Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity
dc.creator.none.fl_str_mv Fuertes, Mercedes Beatriz
Girart, Maria Victoria
Molinero, Luciana Lorena
Domaica, Carolina Ines
Rossi, Lucas Ezequiel
Barrio, Maria Marcela
Mordoh, Jose
Rabinovich, Gabriel Adrián
Zwirner, Norberto Walter
author Fuertes, Mercedes Beatriz
author_facet Fuertes, Mercedes Beatriz
Girart, Maria Victoria
Molinero, Luciana Lorena
Domaica, Carolina Ines
Rossi, Lucas Ezequiel
Barrio, Maria Marcela
Mordoh, Jose
Rabinovich, Gabriel Adrián
Zwirner, Norberto Walter
author_role author
author2 Girart, Maria Victoria
Molinero, Luciana Lorena
Domaica, Carolina Ines
Rossi, Lucas Ezequiel
Barrio, Maria Marcela
Mordoh, Jose
Rabinovich, Gabriel Adrián
Zwirner, Norberto Walter
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Melanoma
Nk Cells
Cancer
Cell Line Tumor
Mica
topic Melanoma
Nk Cells
Cancer
Cell Line Tumor
Mica
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Most tumors grow in immunocompetent hosts despite expressing NKG2D ligands (NKG2DLs) such as the MHC class I chain-related genes A and B (MICA/B). However, their participation in tumor cell evasion is still not completely understood. Here we demonstrate that several human melanomas (cell lines and freshly isolated metastases) do not express MICA on the cell surface but have intracellular deposits of this NKG2DL. Susceptibility to NK cell-mediated cytotoxicity correlated with the ratio of NKG2DLs to HLA class I molecules but not with the amounts of MICA on the cell surface of tumor cells. Transfection-mediated overexpression of MICA restored cell surface expression and resulted in an increased in vitro cytotoxicity and IFN-gamma secretion by human NK cells. In xenografted nude mice, these melanomas exhibited a delayed growth and extensive in vivo apoptosis. Retardation of tumor growth was due to NK cell-mediated antitumor activity against MICA-transfected tumors, given that this effect was not observed in NK cell-depleted mice. Also, mouse NK cells killed MICA-overexpressing melanomas in vitro. A mechanistic analysis revealed the retention of MICA in the endoplasmic reticulum, an effect that was associated with accumulation of endoH-sensitive (immature) forms of MICA, retrograde transport to the cytoplasm, and degradation by the proteasome. Our study identifies a novel strategy developed by melanoma cells to evade NK cell-mediated immune surveillance based on the intracellular sequestration of immature forms of MICA in the endoplasmic reticulum. Furthermore, this tumor immune escape strategy can be overcome by gene therapy approaches aimed at overexpressing MICA on tumor cells,
Fil: Fuertes, Mercedes Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Girart, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Molinero, Luciana Lorena. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina
Fil: Domaica, Carolina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Rossi, Lucas Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Barrio, Maria Marcela. Fundación P/la Invest.y Prevención del Cancer. Centro de Investigaciones Oncologicas; Argentina
Fil: Mordoh, Jose. Fundación Instituto Leloir; Argentina. Fundación P/la Invest.y Prevención del Cancer. Centro de Investigaciones Oncologicas; Argentina
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
Fil: Zwirner, Norberto Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina
description Most tumors grow in immunocompetent hosts despite expressing NKG2D ligands (NKG2DLs) such as the MHC class I chain-related genes A and B (MICA/B). However, their participation in tumor cell evasion is still not completely understood. Here we demonstrate that several human melanomas (cell lines and freshly isolated metastases) do not express MICA on the cell surface but have intracellular deposits of this NKG2DL. Susceptibility to NK cell-mediated cytotoxicity correlated with the ratio of NKG2DLs to HLA class I molecules but not with the amounts of MICA on the cell surface of tumor cells. Transfection-mediated overexpression of MICA restored cell surface expression and resulted in an increased in vitro cytotoxicity and IFN-gamma secretion by human NK cells. In xenografted nude mice, these melanomas exhibited a delayed growth and extensive in vivo apoptosis. Retardation of tumor growth was due to NK cell-mediated antitumor activity against MICA-transfected tumors, given that this effect was not observed in NK cell-depleted mice. Also, mouse NK cells killed MICA-overexpressing melanomas in vitro. A mechanistic analysis revealed the retention of MICA in the endoplasmic reticulum, an effect that was associated with accumulation of endoH-sensitive (immature) forms of MICA, retrograde transport to the cytoplasm, and degradation by the proteasome. Our study identifies a novel strategy developed by melanoma cells to evade NK cell-mediated immune surveillance based on the intracellular sequestration of immature forms of MICA in the endoplasmic reticulum. Furthermore, this tumor immune escape strategy can be overcome by gene therapy approaches aimed at overexpressing MICA on tumor cells,
publishDate 2008
dc.date.none.fl_str_mv 2008
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/11336/25922
Fuertes, Mercedes Beatriz; Girart, Maria Victoria; Molinero, Luciana Lorena; Domaica, Carolina Ines; Rossi, Lucas Ezequiel; et al.; Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity; American Association of Immunologists; Journal of Immunology; 180; 7; 2008; 4606-4614
0022-1767
1550-6606
CONICET Digital
CONICET
url http://hdl.handle.net/11336/25922
identifier_str_mv Fuertes, Mercedes Beatriz; Girart, Maria Victoria; Molinero, Luciana Lorena; Domaica, Carolina Ines; Rossi, Lucas Ezequiel; et al.; Intracellular retention of the NKG2D ligand MHC Class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity; American Association of Immunologists; Journal of Immunology; 180; 7; 2008; 4606-4614
0022-1767
1550-6606
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://www.jimmunol.org/content/180/7/4606
info:eu-repo/semantics/altIdentifier/doi/10.4049/jimmunol.180.7.4606
info:eu-repo/semantics/altIdentifier/pmid/18354183
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
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dc.publisher.none.fl_str_mv American Association of Immunologists
publisher.none.fl_str_mv American Association of Immunologists
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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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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