Title |
IRF1 and NF-kB Restore MHC Class I-Restricted Tumor Antigen Processing and Presentation to Cytotoxic T Cells in Aggressive Neuroblastoma
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Published in |
PLOS ONE, October 2012
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DOI | 10.1371/journal.pone.0046928 |
Pubmed ID | |
Authors |
Silvia Lorenzi, Matteo Forloni, Loredana Cifaldi, Chiara Antonucci, Arianna Citti, Renata Boldrini, Marco Pezzullo, Aurora Castellano, Vincenzo Russo, Pierre van der Bruggen, Patrizio Giacomini, Franco Locatelli, Doriana Fruci |
Abstract |
Neuroblastoma (NB), the most common solid extracranial cancer of childhood, displays a remarkable low expression of Major Histocompatibility Complex class I (MHC-I) and Antigen Processing Machinery (APM) molecules, including Endoplasmic Reticulum (ER) Aminopeptidases, and poorly presents tumor antigens to Cytotoxic T Lymphocytes (CTL). We have previously shown that this is due to low expression of the transcription factor NF-kB p65. Herein, we show that not only NF-kB p65, but also the Interferon Regulatory Factor 1 (IRF1) and certain APM components are low in a subset of NB cell lines with aggressive features. Whereas single transfection with either IRF1, or NF-kB p65 is ineffective, co-transfection results in strong synergy and substantial reversion of the MHC-I/APM-low phenotype in all NB cell lines tested. Accordingly, linked immunohistochemistry expression patterns between nuclear IRF1 and p65 on the one hand, and MHC-I on the other hand, were observed in vivo. Absence and presence of the three molecules neatly segregated between high-grade and low-grade NB, respectively. Finally, APM reconstitution by double IRF1/p65 transfection rendered a NB cell line susceptible to killing by anti MAGE-A3 CTLs, lytic efficiency comparable to those seen upon IFN-γ treatment. This is the first demonstration that a complex immune escape phenotype can be rescued by reconstitution of a limited number of master regulatory genes. These findings provide molecular insight into defective MHC-I expression in NB cells and provide the rational for T cell-based immunotherapy in NB variants refractory to conventional therapy. |
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Geographical breakdown
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Demographic breakdown
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Student > Master | 14 | 15% |
Student > Ph. D. Student | 12 | 13% |
Student > Bachelor | 9 | 10% |
Student > Doctoral Student | 4 | 4% |
Other | 11 | 12% |
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Unspecified | 4 | 4% |
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