PMID- 23071666
OWN - NLM
STAT- MEDLINE
DCOM- 20130411
LR  - 20220331
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 10
DP  - 2012
TI  - IRF1 and NF-kB restore MHC class I-restricted tumor antigen processing and 
      presentation to cytotoxic T cells in aggressive neuroblastoma.
PG  - e46928
LID - 10.1371/journal.pone.0046928 [doi]
LID - e46928
AB  - 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-gamma 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.
FAU - Lorenzi, Silvia
AU  - Lorenzi S
AD  - Paediatric Haematology/Oncology Department, Bambino Gesu Children's Hospital, 
      IRCCS, Rome, Italy.
FAU - Forloni, Matteo
AU  - Forloni M
FAU - Cifaldi, Loredana
AU  - Cifaldi L
FAU - Antonucci, Chiara
AU  - Antonucci C
FAU - Citti, Arianna
AU  - Citti A
FAU - Boldrini, Renata
AU  - Boldrini R
FAU - Pezzullo, Marco
AU  - Pezzullo M
FAU - Castellano, Aurora
AU  - Castellano A
FAU - Russo, Vincenzo
AU  - Russo V
FAU - van der Bruggen, Pierre
AU  - van der Bruggen P
FAU - Giacomini, Patrizio
AU  - Giacomini P
FAU - Locatelli, Franco
AU  - Locatelli F
FAU - Fruci, Doriana
AU  - Fruci D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121005
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antigens)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (IRF1 protein, human)
RN  - 0 (Interferon Regulatory Factor-1)
RN  - 0 (MAGEA3 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Transcription Factor RelA)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Antigen Presentation/drug effects/*immunology
MH  - Antigens/genetics/immunology/metabolism
MH  - Antigens, Neoplasm/genetics/immunology/metabolism
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Histocompatibility Antigens Class I/*immunology/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Interferon Regulatory Factor-1/genetics/*immunology/metabolism
MH  - Interferon-gamma/immunology/pharmacology
MH  - Jurkat Cells
MH  - Neoplasm Proteins/genetics/immunology/metabolism
MH  - Neuroblastoma/immunology/metabolism/pathology
MH  - RNA Interference
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - T-Lymphocytes, Cytotoxic/*immunology/metabolism
MH  - Transcription Factor RelA/genetics/*immunology/metabolism
MH  - Transfection
MH  - Up-Regulation/immunology
PMC - PMC3465322
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/10/17 06:00
MHDA- 2013/04/12 06:00
PMCR- 2012/10/05
CRDT- 2012/10/17 06:00
PHST- 2012/04/19 00:00 [received]
PHST- 2012/09/06 00:00 [accepted]
PHST- 2012/10/17 06:00 [entrez]
PHST- 2012/10/17 06:00 [pubmed]
PHST- 2013/04/12 06:00 [medline]
PHST- 2012/10/05 00:00 [pmc-release]
AID - PONE-D-12-11015 [pii]
AID - 10.1371/journal.pone.0046928 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(10):e46928. doi: 10.1371/journal.pone.0046928. Epub 2012 Oct 5.