Development of a potent melanoma vaccine capable of stimulating CD8+ T-cells independently of dendritic cells in a mouse model
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At present, there are no vaccines approved for the prevention or treatment of malignant melanoma, despite the amount of time and resources that has been invested. In this study, we aimed to develop a self-contained vaccine capable of directly stimulating anticancer CD8+ T-cell immune responses. To achieve this, three whole-cell melanoma vaccines were developed expressing 4-1BBL or B7.1 T-cell co-stimulatory molecules individually or in combination. The ability of engineered vaccine cell lines to stimulate potent anticancer immune responses in C57BL/6 mice was assessed. Mice vaccinated with cells overexpressing both 4-1BBL and B7.1 (B16-F10-4-1BBL-B7.1-IFNγ/β anticancer vaccine) displayed the greatest increases in CD8+ T-cell populations (1.9-fold increase versus control within spleens), which were efficiently activated following antigenic stimulation, resulting in a 10.7-fold increase in cancer cell cytotoxicity relative to control. The enhanced immune responses in B16-F10-4-1BBL-B7.1-IFNγ/β-vaccinated mice translated into highly efficient rejection of live tumour burdens and conferred long-term protection against repeated tumour challenges, which were likely due to enhanced effector memory T-cell populations. Similar results were observed when dendritic cell (DC)-deficient LTα−/− mice were treated with the B16-F10-4-1BBL-B7.1-IFNγ/β anticancer vaccine, suggesting that the vaccine can directly stimulate CD8+ T-cell responses in the context of severely reduced DCs. This study shows that the B16-F10-4-1BBL-B7.1-IFNγ/β anticancer vaccine acted as a highly effective antigen-presenting cell and is likely to be able to directly stimulate CD8+ T-cells, without requiring co-stimulatory signals from either CD4+ T-cells or DCs, and warrants translation of this technology into the clinical setting.
KeywordsVaccine Melanoma Immune response Cytotoxic T-cells Effector memory CD8+ T-cells
Cytotoxic T lymphocyte
Mixed lymphocyte culture
Central memory CD8+ T-cell
Effector memory CD8+ T-cell
The authors would like to acknowledge Dr. Brendan Hill and Nigel Middlebrooke at Premion Cancer Care, Southport, for assisting with the use of the irradiator. This study was supported by Genvax Pty. Ltd. Katie L. Powell was supported by an Australian Postgraduate Award.
Conflict of interest
S.J. Ralph is the Director of Genvax Pty. Ltd., and this study was supported by funding from Genvax Pty. Ltd. S.J. Ralph is a consultant and inventor on patents related to the commercialisation of cancer vaccines including some technology described herein. S.J. Ralph and K.L. Powell have filed a patent relating to the material presented. A.S. Stephens has no conflict of interest to declare.
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