IRF1 and NF-kB restore MHC class I-restricted tumor antigen processing and presentation to cytotoxic T cells in aggressive neuroblastoma.
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.
Paediatric Haematology/Oncology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Silvia
S
Lorenzi
Matteo
M
Forloni
Loredana
L
Cifaldi
Chiara
C
Antonucci
Arianna
A
Citti
Renata
R
Boldrini
Marco
M
Pezzullo
Aurora
A
Castellano
Vincenzo
V
Russo
Pierre
P
van der Bruggen
Patrizio
P
Giacomini
Franco
F
Locatelli
Doriana
D
Fruci
D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D000941:Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D019169:Jurkat Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009447:Neuroblastoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000276:immunology
D000941:Antigens; D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D051996:Transcription Factor RelA; D007371:Interferon-gamma