MYCN is an immunosuppressive oncogene dampening the expression of ligands for NK-cell-activating receptors in human high-risk neuroblastoma

Elisa Brandetti, Irene Veneziani, Ombretta Melaiu, Annalisa Pezzolo, Aurora Castellano, Renata Boldrini, Elisa Ferretti, Doriana Fruci, Lorenzo Moretta, Vito Pistoia, Franco Locatelli, Loredana Cifaldi

Research output: Contribution to journalArticle

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor occurring in childhood. Amplification of the MYCN oncogene is associated with poor prognosis. Downregulation on NB cells of ligands recognized by Natural Killer (NK) cell-activating receptors, involved in tumor cell recognition and lysis, may contribute to tumor progression and relapse. Here, we demonstrate that in human NB cell lines MYCN expression inversely correlates with that of ligands recognized by NKG2D and DNAM1 activating receptors in human NB cell lines. In the MYCN-inducible Tet-21/N cell line, downregulation of MYCN resulted in enhanced expression of the activating ligands MICA, ULBPs and PVR, which rendered tumor cells more susceptible to recognition and lysis mediated by NK cells. Conversely, a MYCN non-amplified NB cell line transfected with MYCN showed an opposite behavior compared with control cells. Consistent with these findings, an inverse correlation was detected between the expression of MYCN and that of ligands for NK-cell-activating receptors in 12 NB patient specimens both at mRNA and protein levels. Taken together, these results provide the first demonstration that MYCN acts as an immunosuppressive oncogene in NB cells that negatively regulates the expression of ligands for NKG2D and DNAM-1 NK-cell-activating receptors. Our study provides a clue to exploit MYCN expression levels as a biomarker to predict the efficacy of NK-cell-based immunotherapy in NB patients.

Original languageEnglish
Pages (from-to)e1316439
JournalOncoImmunology
Volume6
Issue number6
DOIs
Publication statusPublished - 2017

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Natural Killer Cell Receptors
Immunosuppressive Agents
Neuroblastoma
Oncogenes
Ligands
Cell Line
Natural Killer Cells
Neoplasms
Down-Regulation
Immunotherapy
Biomarkers
Recurrence
Messenger RNA

Keywords

  • Journal Article

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MYCN is an immunosuppressive oncogene dampening the expression of ligands for NK-cell-activating receptors in human high-risk neuroblastoma. / Brandetti, Elisa; Veneziani, Irene; Melaiu, Ombretta; Pezzolo, Annalisa; Castellano, Aurora; Boldrini, Renata; Ferretti, Elisa; Fruci, Doriana; Moretta, Lorenzo; Pistoia, Vito; Locatelli, Franco; Cifaldi, Loredana.

In: OncoImmunology, Vol. 6, No. 6, 2017, p. e1316439.

Research output: Contribution to journalArticle

Brandetti, E, Veneziani, I, Melaiu, O, Pezzolo, A, Castellano, A, Boldrini, R, Ferretti, E, Fruci, D, Moretta, L, Pistoia, V, Locatelli, F & Cifaldi, L 2017, 'MYCN is an immunosuppressive oncogene dampening the expression of ligands for NK-cell-activating receptors in human high-risk neuroblastoma', OncoImmunology, vol. 6, no. 6, pp. e1316439. https://doi.org/10.1080/2162402X.2017.1316439
Brandetti, Elisa ; Veneziani, Irene ; Melaiu, Ombretta ; Pezzolo, Annalisa ; Castellano, Aurora ; Boldrini, Renata ; Ferretti, Elisa ; Fruci, Doriana ; Moretta, Lorenzo ; Pistoia, Vito ; Locatelli, Franco ; Cifaldi, Loredana. / MYCN is an immunosuppressive oncogene dampening the expression of ligands for NK-cell-activating receptors in human high-risk neuroblastoma. In: OncoImmunology. 2017 ; Vol. 6, No. 6. pp. e1316439.
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T1 - MYCN is an immunosuppressive oncogene dampening the expression of ligands for NK-cell-activating receptors in human high-risk neuroblastoma

AU - Brandetti, Elisa

AU - Veneziani, Irene

AU - Melaiu, Ombretta

AU - Pezzolo, Annalisa

AU - Castellano, Aurora

AU - Boldrini, Renata

AU - Ferretti, Elisa

AU - Fruci, Doriana

AU - Moretta, Lorenzo

AU - Pistoia, Vito

AU - Locatelli, Franco

AU - Cifaldi, Loredana

PY - 2017

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N2 - Neuroblastoma (NB) is the most common extracranial solid tumor occurring in childhood. Amplification of the MYCN oncogene is associated with poor prognosis. Downregulation on NB cells of ligands recognized by Natural Killer (NK) cell-activating receptors, involved in tumor cell recognition and lysis, may contribute to tumor progression and relapse. Here, we demonstrate that in human NB cell lines MYCN expression inversely correlates with that of ligands recognized by NKG2D and DNAM1 activating receptors in human NB cell lines. In the MYCN-inducible Tet-21/N cell line, downregulation of MYCN resulted in enhanced expression of the activating ligands MICA, ULBPs and PVR, which rendered tumor cells more susceptible to recognition and lysis mediated by NK cells. Conversely, a MYCN non-amplified NB cell line transfected with MYCN showed an opposite behavior compared with control cells. Consistent with these findings, an inverse correlation was detected between the expression of MYCN and that of ligands for NK-cell-activating receptors in 12 NB patient specimens both at mRNA and protein levels. Taken together, these results provide the first demonstration that MYCN acts as an immunosuppressive oncogene in NB cells that negatively regulates the expression of ligands for NKG2D and DNAM-1 NK-cell-activating receptors. Our study provides a clue to exploit MYCN expression levels as a biomarker to predict the efficacy of NK-cell-based immunotherapy in NB patients.

AB - Neuroblastoma (NB) is the most common extracranial solid tumor occurring in childhood. Amplification of the MYCN oncogene is associated with poor prognosis. Downregulation on NB cells of ligands recognized by Natural Killer (NK) cell-activating receptors, involved in tumor cell recognition and lysis, may contribute to tumor progression and relapse. Here, we demonstrate that in human NB cell lines MYCN expression inversely correlates with that of ligands recognized by NKG2D and DNAM1 activating receptors in human NB cell lines. In the MYCN-inducible Tet-21/N cell line, downregulation of MYCN resulted in enhanced expression of the activating ligands MICA, ULBPs and PVR, which rendered tumor cells more susceptible to recognition and lysis mediated by NK cells. Conversely, a MYCN non-amplified NB cell line transfected with MYCN showed an opposite behavior compared with control cells. Consistent with these findings, an inverse correlation was detected between the expression of MYCN and that of ligands for NK-cell-activating receptors in 12 NB patient specimens both at mRNA and protein levels. Taken together, these results provide the first demonstration that MYCN acts as an immunosuppressive oncogene in NB cells that negatively regulates the expression of ligands for NKG2D and DNAM-1 NK-cell-activating receptors. Our study provides a clue to exploit MYCN expression levels as a biomarker to predict the efficacy of NK-cell-based immunotherapy in NB patients.

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