Abstract
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.
Highlights
Virus-like particles (VLP), nanoparticles that self-assemble from capsid proteins of viruses, are stable, highly immunogenic, and proven safe to use in vaccine formulations [1, 2]
VLP acquired by antigen-presenting cells (APC), such as dendritic cells (DC), can induce a cellular antitumour immune response, which can be utilized for cancer immunotherapy
Antigens acquired externally are usually processed onto major histocompatibility complex- (MHC-) II; we have shown that tumour antigens delivered by rabbit haemorrhagic disease virus (RHDV) VLP can be cross-presented onto MHC-I [10]
Summary
Virus-like particles (VLP), nanoparticles that self-assemble from capsid proteins of viruses, are stable, highly immunogenic, and proven safe to use in vaccine formulations [1, 2]. While VLP can be used to provide protection against the parent virus, they can be exploited as a vaccine platform against a variety of diseases by delivering foreign antigens [3, 4]. VLP acquired by antigen-presenting cells (APC), such as dendritic cells (DC), can induce a cellular antitumour immune response, which can be utilized for cancer immunotherapy. This study used VLP derived from the rabbit haemorrhagic disease virus (RHDV) which is composed of 180 copies of the viral capsid protein VP60 [3]. The RHDV VLP can be engineered to recombinantly express repetitive tumour epitopes, such as the glycoprotein 100 (gp100) peptide KVPRNQDWL (gp10025–33). The RHDV VLP can be engineered to recombinantly express repetitive tumour epitopes, such as the glycoprotein 100 (gp100) peptide KVPRNQDWL (gp10025–33). gp100 is a widely studied melanoma-associated antigen that is involved in melanosome maturation and melanin synthes2iDs b[5r]e.sTtrhicetegdp1e0p0it2o5p–3e3 peptide that has used in shown this study is an Hpromise in tumour
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