Liposomal Nanovaccine Containing α-Galactosylceramide and Ganglioside GM3 Stimulates Robust CD8 + T Cell Responses via CD169 + Macrophages and cDC1.

Successful anti-cancer vaccines aim to prime and reinvigorate cytotoxic T cells and should therefore comprise a potent antigen and adjuvant. Antigen targeting to splenic CD169 ⁺ macrophages was shown to induce robust CD8 ⁺ T cell responses via antigen transfer to cDC1. Interestingly, CD169 ⁺ macrophages can also activate type I natural killer T-cells (NKT). NKT activation via ligands such as α-galactosylceramide (αGC) serve as natural adjuvants through dendritic cell activation. Here, we incorporated ganglioside GM3 and αGC in ovalbumin (OVA) protein-containing liposomes to achieve both CD169 ⁺ targeting and superior DC activation. The systemic delivery of GM3-αGC-OVA liposomes resulted in specific uptake by splenic CD169 ⁺ macrophages, stimulated strong IFNγ production by NKT and NK cells and coincided with the maturation of cDC1 and significant IL-12 production. Strikingly, superior induction of OVA-specific CD8 ⁺ T cells was detected after immunization with GM3-αGC-OVA liposomes. CD8 ⁺ T cell activation, but not B cell activation, was dependent on CD169 ⁺ macrophages and cDC1, while activation of NKT and NK cells were partially mediated by cDC1. In summary, GM3-αGC antigen-containing liposomes are a potent vaccination platform that promotes the interaction between different immune cell populations, resulting in strong adaptive immunity and therefore emerge as a promising anti-cancer vaccination strategy.