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Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming

Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming
Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming
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.
fusogenic proteins, dendritic cells, immunotherapy, syncitia, t-cell priming
0969-7128
138-149
Errington, F.
d0825a1b-2d39-4dbd-a58c-de59e6c6dc0b
Jones, J.
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Merrick, A.
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Bateman, A.
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Harrington, K.
9d77d2a9-dc4d-4ee7-b9b4-adb8cd992610
Gough, M.
d326c005-44ca-442c-9be0-57de158ce117
O'Donell, D.
bd9f3567-4d51-4ba9-8876-d407a2450454
Selby, P.
3c685c56-72fd-4a25-b4b8-120074cc087b
Vile, R.
f363088d-5c80-4d4e-bfd5-340cadd8f7de
Melcher, A.
e8655568-0594-4239-8661-b05900e49337
Errington, F.
d0825a1b-2d39-4dbd-a58c-de59e6c6dc0b
Jones, J.
5ca0d91a-d5f9-4d00-834d-46c550240a13
Merrick, A.
32c054ca-e5f6-47bc-8442-811acb43349b
Bateman, A.
0a712ec4-c2b7-408f-beaa-cc639988aa03
Harrington, K.
9d77d2a9-dc4d-4ee7-b9b4-adb8cd992610
Gough, M.
d326c005-44ca-442c-9be0-57de158ce117
O'Donell, D.
bd9f3567-4d51-4ba9-8876-d407a2450454
Selby, P.
3c685c56-72fd-4a25-b4b8-120074cc087b
Vile, R.
f363088d-5c80-4d4e-bfd5-340cadd8f7de
Melcher, A.
e8655568-0594-4239-8661-b05900e49337

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).

Record type: Article

Abstract

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.

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More information

Published date: 2006
Keywords: fusogenic proteins, dendritic cells, immunotherapy, syncitia, t-cell priming

Identifiers

Local EPrints ID: 26298
URI: http://eprints.soton.ac.uk/id/eprint/26298
ISSN: 0969-7128
PURE UUID: 67ca7a2b-ddf3-4d2d-a858-2c0dc4ee56f7

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Date deposited: 07 Apr 2006
Last modified: 18 Mar 2024 17:33

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Contributors

Author: F. Errington
Author: J. Jones
Author: A. Merrick
Author: A. Bateman
Author: K. Harrington
Author: M. Gough
Author: D. O'Donell
Author: P. Selby
Author: R. Vile
Author: A. Melcher

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