Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming
Errington, F., Jones, J., Merrick, A., Bateman, A., Harrington, K., Gough, M., O'Donell, D., Selby, P., Vile, R. and Melcher, A. (2006) Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming. Gene Therapy, 13, (2), 138-149. (doi:10.1038/sj.gt.3302609).
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Fusogenic membrane glycoproteins (FMG) are a family of viral genes that, when expressed in tumour cells, trigger extensive cell to cell fusion and subsequent cell death. Gene therapy approaches using FMG are also potentially immunogenic, since syncitia generated ex vivo can be therapeutic as antitumour vaccines in murine models. This study has addressed the mechanisms responsible for the immunogenicity of FMG-mediated cell death, and its applicability to human immune priming. We show that fusion of human Mel888 melanoma cells following transfection with FMG can reverse the suppressive effects of Mel888 on dendritic cells (DC) phenotype, and potentiate IL-12 production by DC on activation in a cell contact-dependent manner. DC loaded with fusing, but not intact, tumour cells primed a naive, tumour-specific cytotoxic T-cell response, which was MHC class I-restricted and associated with production of high levels of IFN and, later, IL-5. Fusing cells were an effective source of antigen for DC cross-priming and presentation of the melanoma-specific antigen gp100 to a specific T-cell clone. These data show, in a human system, that FMG represent an immunogenic, as well as cytotoxic, gene therapy for cancer, reversing the inhibitory effects of tumour cells on DC to potentiate IL-12 production and naive T-cell priming.
|Keywords:||fusogenic proteins, dendritic cells, immunotherapy, syncitia, t-cell priming|
|Subjects:||R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Q Science > QR Microbiology > QR180 Immunology
Q Science > QH Natural history > QH426 Genetics
|Divisions:||University Structure - Pre August 2011 > School of Medicine > Infection, Inflammation and Repair
|Date Deposited:||07 Apr 2006|
|Last Modified:||31 May 2011 23:44|
|Contributors:||Errington, F. (Author)
Jones, J. (Author)
Merrick, A. (Author)
Bateman, A. (Author)
Harrington, K. (Author)
Gough, M. (Author)
O'Donell, D. (Author)
Selby, P. (Author)
Vile, R. (Author)
Melcher, A. (Author)
|Contact Email Address:||email@example.com|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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