PloS one, 2012-10, Vol.7 (10), p.e46928-e46928
2012
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- Autor(en) / Beteiligte
- Titel
- IRF1 and NF-kB restore MHC class I-restricted tumor antigen processing and presentation to cytotoxic T cells in aggressive neuroblastoma
- Ist Teil von
- PloS one, 2012-10, Vol.7 (10), p.e46928-e46928
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0046928Titel-ID: cdi_plos_journals_1326720526
- Format
- –
- Schlagworte
- Aminopeptidase, Antigen (tumor-associated), Antigen presentation, Antigen Presentation - drug effects, Antigen Presentation - immunology, Antigen processing, Antigens, Antigens - genetics, Antigens - immunology, Antigens - metabolism, Antigens, Neoplasm - genetics, Antigens, Neoplasm - immunology, Antigens, Neoplasm - metabolism, Biological response modifiers, Biology, Biotechnology, Blotting, Western, Cancer, Cancer therapies, Cell Line, Tumor, Chemotherapy, Children, Cytotoxicity, Endoplasmic reticulum, Gene amplification, Gene expression, Hematology, Histocompatibility Antigens Class I - immunology, Histocompatibility Antigens Class I - metabolism, Humans, Immunohistochemistry, Immunotherapy, Interferon, Interferon regulatory factor, Interferon regulatory factor 1, Interferon Regulatory Factor-1 - genetics, Interferon Regulatory Factor-1 - immunology, Interferon Regulatory Factor-1 - metabolism, Interferon-gamma - immunology, Interferon-gamma - pharmacology, Jurkat Cells, Kinases, Lymphocytes, Lymphocytes T, Lymphoma, Machinery and equipment, Major histocompatibility complex, Medicine, Melanoma, Neoplasm Proteins - genetics, Neoplasm Proteins - immunology, Neoplasm Proteins - metabolism, Neuroblastoma, Neuroblastoma - immunology, Neuroblastoma - metabolism, Neuroblastoma - pathology, NF-κB protein, Oncology, Pathology, Peptides, Reverse Transcriptase Polymerase Chain Reaction, Reversion, RNA Interference, T cells, T-Lymphocytes, Cytotoxic - immunology, T-Lymphocytes, Cytotoxic - metabolism, Transcription Factor RelA - genetics, Transcription Factor RelA - immunology, Transcription Factor RelA - metabolism, Transfection, Tumor antigens, Tumors, Up-Regulation - immunology, γ-Interferon