Targeted co-delivery of tumor antigen and alpha-galactosylceramide to CD141(+) dendritic cells induces a potent tumor antigen-specific human CD8(+) T cell response in human immune system mice

Huang, J.; Zhou, J.; Ghinnagow, R.; Seki, T.; Iketani, S.; Soulard, D.; Paczkowski, P.; Tsuji, Y.; MacKay, S.; Cruz, L.J.; Trottein, F.; Tsuji, M.

doi:doi:10.3389/fimmu.2020.02043

Active co-delivery of tumor antigens (Ag) and alpha-galactosylceramide (alpha-GalCer), a potent agonist for invariant Natural Killer T (iNKT) cells, to cross-priming CD8 alpha(+) dendritic cells (DCs) was previously shown to promote strong anti-tumor responses in mice. Here, we designed a nanoparticle-based vaccine able to target human CD141(+) (BDCA3(+)) DCs - the equivalent of murine CD8 alpha(+) DCs - and deliver both tumor Ag (Melan A) and alpha-GalCer. This nanovaccine was inoculated into humanized mice that mimic the human immune system (HIS) and possess functionaliNKT cells and CD8(+) T cells, called HIS-CD8/NKT mice. We found that multiple immunizations of HIS-CD8/NKT mice with the nanovaccine resulted in the activation and/or expansion of human CD141(+) DCs andiNKT cells and ultimately elicited a potent Melan-A-specific CD8(+) T cell response, as determined by tetramer staining and ELISpot assay. Single-cell proteomics further detailed the highly polyfunctional CD8(+) T...Show moreActive co-delivery of tumor antigens (Ag) and alpha-galactosylceramide (alpha-GalCer), a potent agonist for invariant Natural Killer T (iNKT) cells, to cross-priming CD8 alpha(+) dendritic cells (DCs) was previously shown to promote strong anti-tumor responses in mice. Here, we designed a nanoparticle-based vaccine able to target human CD141(+) (BDCA3(+)) DCs - the equivalent of murine CD8 alpha(+) DCs - and deliver both tumor Ag (Melan A) and alpha-GalCer. This nanovaccine was inoculated into humanized mice that mimic the human immune system (HIS) and possess functionaliNKT cells and CD8(+) T cells, called HIS-CD8/NKT mice. We found that multiple immunizations of HIS-CD8/NKT mice with the nanovaccine resulted in the activation and/or expansion of human CD141(+) DCs andiNKT cells and ultimately elicited a potent Melan-A-specific CD8(+) T cell response, as determined by tetramer staining and ELISpot assay. Single-cell proteomics further detailed the highly polyfunctional CD8(+) T cells induced by the nanovaccine and revealed their predictive potential for vaccine potency. This finding demonstrates for the first time the unique ability of humaniNKT cells to license cross-priming DCsin vivoand adds a new dimension to the current strategy of cancer vaccine development.Show less

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Targeted co-delivery of tumor antigen and alpha-galactosylceramide to CD141(+) dendritic cells induces a potent tumor antigen-specific human CD8(+) T cell response in human immune system mice