TY - JOUR T1 - IRF1 and NF-kB Restore MHC Class I-Restricted Tumor Antigen Processing and Presentation to Cytotoxic T Cells in Aggressive Neuroblastoma A1 - Lorenzi, Silvia A1 - Forloni, Matteo A1 - Cifaldi, Loredana A1 - Antonucci, Chiara A1 - Citti, Arianna A1 - Boldrini, Renata A1 - Pezzullo, Marco A1 - Castellano, Aurora A1 - Russo, Vincenzo A1 - van der Bruggen, Pierre A1 - Giacomini, Patrizio A1 - Locatelli, Franco A1 - Fruci, Doriana Y1 - 2012/10/05 N2 - 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. JF - PLOS ONE JA - PLOS ONE VL - 7 IS - 10 UR - https://doi.org/10.1371/journal.pone.0046928 SP - e46928 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pone.0046928 ER -