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Cancer Immunology Research
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Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors

Irene Veneziani, Paola Infante, Elisa Ferretti, Ombretta Melaiu, Cecilia Battistelli, Valeria Lucarini, Mirco Compagnone, Carmine Nicoletti, Aurora Castellano, Stefania Petrini, Marzia Ognibene, Annalisa Pezzolo, Lucia Di Marcotullio, Roberto Bei, Lorenzo Moretta, Vito Pistoia, Doriana Fruci, Vincenzo Barnaba, Franco Locatelli and Loredana Cifaldi
Irene Veneziani
1Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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  • ORCID record for Irene Veneziani
Paola Infante
2Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
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Elisa Ferretti
3Department of Experimental Medicine, University of Genoa, Genova, Italy.
4Centre of Excellence for Biomedical Research, University of Genoa, Genova, Italy.
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Ombretta Melaiu
1Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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Cecilia Battistelli
5Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.
6Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
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Valeria Lucarini
1Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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Mirco Compagnone
1Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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Carmine Nicoletti
5Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.
7DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
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Aurora Castellano
1Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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Stefania Petrini
8Confocal Microscopy, Core Facility, Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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  • ORCID record for Stefania Petrini
Marzia Ognibene
9Laboratorio Cellule Staminali Post Natali e Terapie Cellulari, IRCCS Giannina Gaslini Institute, Genoa, Italy.
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Annalisa Pezzolo
9Laboratorio Cellule Staminali Post Natali e Terapie Cellulari, IRCCS Giannina Gaslini Institute, Genoa, Italy.
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Lucia Di Marcotullio
5Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.
6Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
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Roberto Bei
10Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata," Rome, Italy.
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Lorenzo Moretta
11Department of Immunology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
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Vito Pistoia
11Department of Immunology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
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Doriana Fruci
1Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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Vincenzo Barnaba
5Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.
12Cellular and Molecular Immunology Unit, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, Rome, Italy.
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Franco Locatelli
1Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
13Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
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Loredana Cifaldi
1Department of Paediatric Haematology/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
10Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata," Rome, Italy.
14Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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  • For correspondence: cifaldi@med.uniroma2.it
DOI: 10.1158/2326-6066.CIR-20-0313 Published February 2021
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Abstract

In this study, we explored whether Nutlin-3a, a well-known, nontoxic small-molecule compound antagonizing the inhibitory interaction of MDM2 with the tumor suppressor p53, may restore ligands for natural killer (NK) cell–activating receptors (NK-AR) on neuroblastoma cells to enhance the NK cell–mediated killing. Neuroblastoma cell lines were treated with Nutlin-3a, and the expression of ligands for NKG2D and DNAM-1 NK-ARs and the neuroblastoma susceptibility to NK cells were evaluated. Adoptive transfer of human NK cells in a xenograft neuroblastoma-bearing NSG murine model was assessed. Two data sets of neuroblastoma patients were explored to correlate p53 expression with ligand expression. Luciferase assays and chromatin immunoprecipitation analysis of p53 functional binding on PVR promoter were performed. Primary neuroblastoma cells were also treated with Nutlin-3a, and neuroblastoma spheroids obtained from one high-risk patient were assayed for NK-cell cytotoxicity. We provide evidence showing that the Nutlin-3a–dependent rescue of p53 function in neuroblastoma cells resulted in (i) increased surface expression of ligands for NK-ARs, thus rendering neuroblastoma cell lines significantly more susceptible to NK cell–mediated killing; (ii) shrinkage of human neuroblastoma tumor masses that correlated with overall survival upon adoptive transfer of NK cells in neuroblastoma-bearing mice; (iii) and increased expression of ligands in primary neuroblastoma cells and boosting of NK cell–mediated disaggregation of neuroblastoma spheroids. We also found that p53 was a direct transcription factor regulating the expression of PVR ligand recognized by DNAM-1. Our findings demonstrated an immunomodulatory role of Nutlin-3a, which might be prospectively used for a novel NK cell–based immunotherapy for neuroblastoma.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:170–83

  • ↵†Deceased.

  • Received April 20, 2020.
  • Revision received September 17, 2020.
  • Accepted December 4, 2020.
  • Published first December 10, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (2)
February 2021
Volume 9, Issue 2
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Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors
Irene Veneziani, Paola Infante, Elisa Ferretti, Ombretta Melaiu, Cecilia Battistelli, Valeria Lucarini, Mirco Compagnone, Carmine Nicoletti, Aurora Castellano, Stefania Petrini, Marzia Ognibene, Annalisa Pezzolo, Lucia Di Marcotullio, Roberto Bei, Lorenzo Moretta, Vito Pistoia, Doriana Fruci, Vincenzo Barnaba, Franco Locatelli and Loredana Cifaldi
Cancer Immunol Res February 1 2021 (9) (2) 170-183; DOI: 10.1158/2326-6066.CIR-20-0313

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Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors
Irene Veneziani, Paola Infante, Elisa Ferretti, Ombretta Melaiu, Cecilia Battistelli, Valeria Lucarini, Mirco Compagnone, Carmine Nicoletti, Aurora Castellano, Stefania Petrini, Marzia Ognibene, Annalisa Pezzolo, Lucia Di Marcotullio, Roberto Bei, Lorenzo Moretta, Vito Pistoia, Doriana Fruci, Vincenzo Barnaba, Franco Locatelli and Loredana Cifaldi
Cancer Immunol Res February 1 2021 (9) (2) 170-183; DOI: 10.1158/2326-6066.CIR-20-0313
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