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Viral fusogenic membrane glycoproteins kill solid tumor cells by nonapoptotic mechanisms that promote cross presentation of tumor antigens by dendritic cells

Viral fusogenic membrane glycoproteins kill solid tumor cells by nonapoptotic mechanisms that promote cross presentation of tumor antigens by dendritic cells
Viral fusogenic membrane glycoproteins kill solid tumor cells by nonapoptotic mechanisms that promote cross presentation of tumor antigens by dendritic cells
Expression of viral fusogenic membrane glycoproteins (FMGs) is a potent strategy for antitumor cytotoxic gene therapy in which tumor cells are fused into large multinucleated syncytia. To understand how local cell killing can potentiate activation of antitumor immune responses, we characterized the mechanism of FMG-mediated cell killing. Here, we show that syncytia are highly ordered structures over 24–48 h but then die through processes that, by multiple morphological and biochemical criteria, bear very little resemblance to classical apoptosis.
Death of syncytia is associated with nuclear fusion and premature chromosome condensation as well as severe ATP depletion and autophagic degeneration, accompanied by release of vesicles reminiscent of exosomes (syncytiosomes). Dying syncytia produce significantly more syncytiosomes than normal cells or cells killed by irradiation, freeze thaw, or osmotic shock. These syncytiosomes also load dendritic cells (DCs) more effectively than exosomes from cells dying by other mechanisms.
Finally, we demonstrate that syncytiosomes from either autologous or allogeneic fusing melanoma cells lead to cross-presentation of a defined tumor antigen, gp100, by DCs to a gp100-specific CTL clone. Cross-presentation was significantly more efficient than that with exosomes from normal, irradiated, or herpes simplex virus thymidine kinase/ganciclovir-killed tumor cells. Therefore, FMG-mediated cell killing combines very effective local tumor cell killing with the potential to be a highly immunogenic method of cytotoxic gene therapy. In addition, these data open the way for novel methods of loading DCs with relevant tumor-associated antigens for vaccine development.
0008-5472
6566-6578
Bateman, Andrew R.
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Harrington, Kevin J.
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Kottke, Tim
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Ahmed, Atique
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Melcher, Alan A.
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Gough, Michael J.
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Linardakis, Emmanouela
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Riddle, David
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Dietz, Allan
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Lohse, Christine M.
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Strome, Scott
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Peterson, Tim
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Simari, Robert
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Vile, Richard G.
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Bateman, Andrew R.
a851558d-8b9b-4020-b148-a239c2b26815
Harrington, Kevin J.
770bae54-a62c-49a6-bf51-5df1349685c4
Kottke, Tim
76d0e0d3-f397-44bd-9e4b-c8dd2961441f
Ahmed, Atique
e60022bd-e2d5-42a3-bb22-8ba40e341407
Melcher, Alan A.
00d1a334-30ea-49e9-b47b-f1792325a835
Gough, Michael J.
e8c96bf4-c50a-4d86-92de-6eada0a0fb1e
Linardakis, Emmanouela
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Riddle, David
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Dietz, Allan
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Lohse, Christine M.
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Strome, Scott
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Peterson, Tim
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Simari, Robert
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Vile, Richard G.
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Bateman, Andrew R., Harrington, Kevin J., Kottke, Tim, Ahmed, Atique, Melcher, Alan A., Gough, Michael J., Linardakis, Emmanouela, Riddle, David, Dietz, Allan, Lohse, Christine M., Strome, Scott, Peterson, Tim, Simari, Robert and Vile, Richard G. (2002) Viral fusogenic membrane glycoproteins kill solid tumor cells by nonapoptotic mechanisms that promote cross presentation of tumor antigens by dendritic cells. Cancer Research, 62 (22), 6566-6578.

Record type: Article

Abstract

Expression of viral fusogenic membrane glycoproteins (FMGs) is a potent strategy for antitumor cytotoxic gene therapy in which tumor cells are fused into large multinucleated syncytia. To understand how local cell killing can potentiate activation of antitumor immune responses, we characterized the mechanism of FMG-mediated cell killing. Here, we show that syncytia are highly ordered structures over 24–48 h but then die through processes that, by multiple morphological and biochemical criteria, bear very little resemblance to classical apoptosis.
Death of syncytia is associated with nuclear fusion and premature chromosome condensation as well as severe ATP depletion and autophagic degeneration, accompanied by release of vesicles reminiscent of exosomes (syncytiosomes). Dying syncytia produce significantly more syncytiosomes than normal cells or cells killed by irradiation, freeze thaw, or osmotic shock. These syncytiosomes also load dendritic cells (DCs) more effectively than exosomes from cells dying by other mechanisms.
Finally, we demonstrate that syncytiosomes from either autologous or allogeneic fusing melanoma cells lead to cross-presentation of a defined tumor antigen, gp100, by DCs to a gp100-specific CTL clone. Cross-presentation was significantly more efficient than that with exosomes from normal, irradiated, or herpes simplex virus thymidine kinase/ganciclovir-killed tumor cells. Therefore, FMG-mediated cell killing combines very effective local tumor cell killing with the potential to be a highly immunogenic method of cytotoxic gene therapy. In addition, these data open the way for novel methods of loading DCs with relevant tumor-associated antigens for vaccine development.

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Published date: 15 November 2002

Identifiers

Local EPrints ID: 26214
URI: http://eprints.soton.ac.uk/id/eprint/26214
ISSN: 0008-5472
PURE UUID: b7cad513-0ef0-4a7e-8855-e703c9cd2b1a

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Date deposited: 20 Apr 2006
Last modified: 25 Nov 2019 19:27

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Contributors

Author: Kevin J. Harrington
Author: Tim Kottke
Author: Atique Ahmed
Author: Alan A. Melcher
Author: Michael J. Gough
Author: Emmanouela Linardakis
Author: David Riddle
Author: Allan Dietz
Author: Christine M. Lohse
Author: Scott Strome
Author: Tim Peterson
Author: Robert Simari
Author: Richard G. Vile

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