Functionalisation of Virus-Like Particles Enhances Antitumour Immune Responses
Virus-like particles (VLP) from the rabbit haemorrhagic disease virus (RHDV) can deliver tumour antigens to induce anticancer immune responses. In this study, we explored how RHDV VLP can be functionalised to enhance the immune response by increasing antigen loading, incorporating linkers to enhance...
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2019/5364632 |
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| author | Katrin Kramer Farah Al-Barwani Margaret A. Baird Vivienne L. Young David S. Larsen Vernon K. Ward Sarah L. Young |
| author_facet | Katrin Kramer Farah Al-Barwani Margaret A. Baird Vivienne L. Young David S. Larsen Vernon K. Ward Sarah L. Young |
| author_sort | Katrin Kramer |
| collection | DOAJ |
| description | Virus-like particles (VLP) from the rabbit haemorrhagic disease virus (RHDV) can deliver tumour antigens to induce anticancer immune responses. In this study, we explored how RHDV VLP can be functionalised to enhance the immune response by increasing antigen loading, incorporating linkers to enhance epitope processing, and targeting receptor-mediated internalisation of VLP. RHDV VLP were developed to deliver up to three copies of gp10025–33 which contained proteasome cleavable linkers to target the correct processing of the epitope. Addition of mono- and dimannosides, conjugated to the surface of the gp100 VLP, would utilise a second pathway of internalisation, mannose receptor mediated, to further augment antigen internalised by phagocytosis/macropinocytosis. In vitro cell culture studies showed that a processing linker at the C-terminus of the epitope (gp100.1LC) induced enhanced T-cell activation (7.3 ng/ml interferon- (IFN-) γ release) compared to no linker (3.0 ng/ml IFN-γ) or the linker at the N-terminus (0.8 ng/ml IFN-γ). VLP delivering two (gp100.2L) or three (gp100.3L) gp100 epitopes induced similar high T-cell activation (7.6 ng/ml IFN-γ) compared to gp100.1LC. An in vivo cytotoxicity assay and a therapeutic tumour trial confirmed that mice vaccinated with either gp100.2L or gp100.3L induced a specific antitumour immune response. Mannosylation of the gp100.2L VLP further enhanced the generated immune response, demonstrated by prolonged survival of mice vaccinated with dimannosylated gp100.2L VLP (D-gp100.2L) by 22 days compared to gp100.2L-vaccinated mice. This study showed that functionalisation of RHDV VLP by addition of an epitope-processing linker and mannosylation of the surface facilitates the efficacy of VLP as vaccination vectors for tumour immunotherapy. |
| format | Article |
| id | doaj-art-0882ebfbf55a4ce38ae4777e914b9228 |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-0882ebfbf55a4ce38ae4777e914b92282025-08-20T03:55:32ZengWileyJournal of Immunology Research2314-88612314-71562019-01-01201910.1155/2019/53646325364632Functionalisation of Virus-Like Particles Enhances Antitumour Immune ResponsesKatrin Kramer0Farah Al-Barwani1Margaret A. Baird2Vivienne L. Young3David S. Larsen4Vernon K. Ward5Sarah L. Young6Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New ZealandBiology Department, Sultan Qaboos University, Muscat, OmanDepartment of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New ZealandDepartment of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New ZealandDepartment of Chemistry, Division of Sciences, University of Otago, Dunedin, New ZealandDepartment of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New ZealandDepartment of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New ZealandVirus-like particles (VLP) from the rabbit haemorrhagic disease virus (RHDV) can deliver tumour antigens to induce anticancer immune responses. In this study, we explored how RHDV VLP can be functionalised to enhance the immune response by increasing antigen loading, incorporating linkers to enhance epitope processing, and targeting receptor-mediated internalisation of VLP. RHDV VLP were developed to deliver up to three copies of gp10025–33 which contained proteasome cleavable linkers to target the correct processing of the epitope. Addition of mono- and dimannosides, conjugated to the surface of the gp100 VLP, would utilise a second pathway of internalisation, mannose receptor mediated, to further augment antigen internalised by phagocytosis/macropinocytosis. In vitro cell culture studies showed that a processing linker at the C-terminus of the epitope (gp100.1LC) induced enhanced T-cell activation (7.3 ng/ml interferon- (IFN-) γ release) compared to no linker (3.0 ng/ml IFN-γ) or the linker at the N-terminus (0.8 ng/ml IFN-γ). VLP delivering two (gp100.2L) or three (gp100.3L) gp100 epitopes induced similar high T-cell activation (7.6 ng/ml IFN-γ) compared to gp100.1LC. An in vivo cytotoxicity assay and a therapeutic tumour trial confirmed that mice vaccinated with either gp100.2L or gp100.3L induced a specific antitumour immune response. Mannosylation of the gp100.2L VLP further enhanced the generated immune response, demonstrated by prolonged survival of mice vaccinated with dimannosylated gp100.2L VLP (D-gp100.2L) by 22 days compared to gp100.2L-vaccinated mice. This study showed that functionalisation of RHDV VLP by addition of an epitope-processing linker and mannosylation of the surface facilitates the efficacy of VLP as vaccination vectors for tumour immunotherapy.http://dx.doi.org/10.1155/2019/5364632 |
| spellingShingle | Katrin Kramer Farah Al-Barwani Margaret A. Baird Vivienne L. Young David S. Larsen Vernon K. Ward Sarah L. Young Functionalisation of Virus-Like Particles Enhances Antitumour Immune Responses Journal of Immunology Research |
| title | Functionalisation of Virus-Like Particles Enhances Antitumour Immune Responses |
| title_full | Functionalisation of Virus-Like Particles Enhances Antitumour Immune Responses |
| title_fullStr | Functionalisation of Virus-Like Particles Enhances Antitumour Immune Responses |
| title_full_unstemmed | Functionalisation of Virus-Like Particles Enhances Antitumour Immune Responses |
| title_short | Functionalisation of Virus-Like Particles Enhances Antitumour Immune Responses |
| title_sort | functionalisation of virus like particles enhances antitumour immune responses |
| url | http://dx.doi.org/10.1155/2019/5364632 |
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