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Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome

SIMPLE SUMMARY: Neuroblastoma (NB) cells adopt several molecular strategies to evade the Natural Killer (NK)-mediated response. Herein, we found that the overexpression of the NF-kB p65 subunit in NB cell lines upregulates the expression of both the death receptor FAS and the activating ligand PVR,...

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Autores principales: Brandetti, Elisa, Focaccetti, Chiara, Pezzolo, Annalisa, Ognibene, Marzia, Folgiero, Valentina, Cotugno, Nicola, Benvenuto, Monica, Palma, Paolo, Manzari, Vittorio, Rossi, Paolo, Fruci, Doriana, Bei, Roberto, Cifaldi, Loredana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430542/
https://www.ncbi.nlm.nih.gov/pubmed/34503178
http://dx.doi.org/10.3390/cancers13174368
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author Brandetti, Elisa
Focaccetti, Chiara
Pezzolo, Annalisa
Ognibene, Marzia
Folgiero, Valentina
Cotugno, Nicola
Benvenuto, Monica
Palma, Paolo
Manzari, Vittorio
Rossi, Paolo
Fruci, Doriana
Bei, Roberto
Cifaldi, Loredana
author_facet Brandetti, Elisa
Focaccetti, Chiara
Pezzolo, Annalisa
Ognibene, Marzia
Folgiero, Valentina
Cotugno, Nicola
Benvenuto, Monica
Palma, Paolo
Manzari, Vittorio
Rossi, Paolo
Fruci, Doriana
Bei, Roberto
Cifaldi, Loredana
author_sort Brandetti, Elisa
collection PubMed
description SIMPLE SUMMARY: Neuroblastoma (NB) cells adopt several molecular strategies to evade the Natural Killer (NK)-mediated response. Herein, we found that the overexpression of the NF-kB p65 subunit in NB cell lines upregulates the expression of both the death receptor FAS and the activating ligand PVR, thus rendering NB cells more susceptible to NK-cell-mediated apoptosis, recognition, and killing. These data could provide a clue for a novel NK-cell-based immunotherapy of NB. In addition, array CGH analysis performed in our cohort of NB patients showed that loss of both the FAS and PVR genes correlated with low survival, thus revealing a novel biomarker predicting the outcome of NB patients. ABSTRACT: High-risk neuroblastoma (NB) is a rare childhood cancer whose aggressiveness is due to a variety of chromosomal genetic aberrations, including those conferring immune evasion. Indeed, NB cells adopt several molecular strategies to evade recognition by the immune system, including the downregulation of ligands for NK-cell-activating receptors. To date, while molecular strategies aimed at enhancing the expression of ligands for NKG2D- and DNAM-1-activating receptors have been explored, no evidence has been reported on the immunomodulatory mechanisms acting on the expression of death receptors such as Fas in NB cells. Here, we demonstrated that transient overexpression of the NF-kB p65 subunit upregulates the surface expression of Fas and PVR, the ligand of DNAM-1, thus making NB cell lines significantly more susceptible to NK-cell-mediated apoptosis, recognition, and killing. In contrast, IFNγ and TNFα treatment, although it induced the upregulation of FAS in NB cells and consequently enhanced NK-cell-mediated apoptosis, triggered immune evasion processes, including the strong upregulation of MHC class I and IDO1, both of which are involved in mechanisms leading to the impairment of a proper NK-cell-mediated killing of NB. In addition, high-resolution array CGH analysis performed in our cohort of NB patients revealed that the loss of FAS and/or PVR genes correlated with low survival independently of the disease stage. Our data identify the status of the FAS and PVR genes as prognostic biomarkers of NB that may predict the efficacy of NK-cell-based immunotherapy of NB. Overall, restoration of surface expression of Fas and PVR, through transient upregulation of NF-kB, may be a clue to a novel NK-cell-based immunotherapy of NB.
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spelling pubmed-84305422021-09-11 Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome Brandetti, Elisa Focaccetti, Chiara Pezzolo, Annalisa Ognibene, Marzia Folgiero, Valentina Cotugno, Nicola Benvenuto, Monica Palma, Paolo Manzari, Vittorio Rossi, Paolo Fruci, Doriana Bei, Roberto Cifaldi, Loredana Cancers (Basel) Article SIMPLE SUMMARY: Neuroblastoma (NB) cells adopt several molecular strategies to evade the Natural Killer (NK)-mediated response. Herein, we found that the overexpression of the NF-kB p65 subunit in NB cell lines upregulates the expression of both the death receptor FAS and the activating ligand PVR, thus rendering NB cells more susceptible to NK-cell-mediated apoptosis, recognition, and killing. These data could provide a clue for a novel NK-cell-based immunotherapy of NB. In addition, array CGH analysis performed in our cohort of NB patients showed that loss of both the FAS and PVR genes correlated with low survival, thus revealing a novel biomarker predicting the outcome of NB patients. ABSTRACT: High-risk neuroblastoma (NB) is a rare childhood cancer whose aggressiveness is due to a variety of chromosomal genetic aberrations, including those conferring immune evasion. Indeed, NB cells adopt several molecular strategies to evade recognition by the immune system, including the downregulation of ligands for NK-cell-activating receptors. To date, while molecular strategies aimed at enhancing the expression of ligands for NKG2D- and DNAM-1-activating receptors have been explored, no evidence has been reported on the immunomodulatory mechanisms acting on the expression of death receptors such as Fas in NB cells. Here, we demonstrated that transient overexpression of the NF-kB p65 subunit upregulates the surface expression of Fas and PVR, the ligand of DNAM-1, thus making NB cell lines significantly more susceptible to NK-cell-mediated apoptosis, recognition, and killing. In contrast, IFNγ and TNFα treatment, although it induced the upregulation of FAS in NB cells and consequently enhanced NK-cell-mediated apoptosis, triggered immune evasion processes, including the strong upregulation of MHC class I and IDO1, both of which are involved in mechanisms leading to the impairment of a proper NK-cell-mediated killing of NB. In addition, high-resolution array CGH analysis performed in our cohort of NB patients revealed that the loss of FAS and/or PVR genes correlated with low survival independently of the disease stage. Our data identify the status of the FAS and PVR genes as prognostic biomarkers of NB that may predict the efficacy of NK-cell-based immunotherapy of NB. Overall, restoration of surface expression of Fas and PVR, through transient upregulation of NF-kB, may be a clue to a novel NK-cell-based immunotherapy of NB. MDPI 2021-08-29 /pmc/articles/PMC8430542/ /pubmed/34503178 http://dx.doi.org/10.3390/cancers13174368 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brandetti, Elisa
Focaccetti, Chiara
Pezzolo, Annalisa
Ognibene, Marzia
Folgiero, Valentina
Cotugno, Nicola
Benvenuto, Monica
Palma, Paolo
Manzari, Vittorio
Rossi, Paolo
Fruci, Doriana
Bei, Roberto
Cifaldi, Loredana
Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome
title Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome
title_full Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome
title_fullStr Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome
title_full_unstemmed Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome
title_short Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome
title_sort enhancement of neuroblastoma nk-cell-mediated lysis through nf-kb p65 subunit-induced expression of fas and pvr, the loss of which is associated with poor patient outcome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430542/
https://www.ncbi.nlm.nih.gov/pubmed/34503178
http://dx.doi.org/10.3390/cancers13174368
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