Targeted Nanoemulsion System for the Delivery of Glycolipid and Antigen to Dendritic Cells as a Potential Immunotherapeutic Vaccine for Cancer Pui Yeng Lam1, Bijun Zeng1, Riccardo Dolcetti1, Ranjeny Thomas1, Graham Leggatt1, Stephen Mattarollo1* 1The University of Queensland Diamantina Institute, Translational Research Institute, Queensland, Australia *Corresponding author Invariant natural killer cells (iNKT) possess potent anti-tumor properties when activated with glycolipid ligands, such as alpha-galactosylceramide (αGalCer). Activation of iNKT cells induces a vast array of immunomodulating cytokines and transactivation of innate and tumor-specific adaptive immune cells. This event is strongly associated with the activities of CD8α+ dendritic cells (DCs). Previous observations using targeted nanoemulsions (TNE) to deliver model OVA antigen to Clec9a-expressing CD8α+ DCs (Clec9a/OVA) have demonstrated a self-adjuvanting effect on DC maturation and the efficient cross-priming of antigen-specific CD8 T cells. Additionally, we have further demonstrated the intricate role for iNKT cells in the maturation of CD8α+ DCs and the enhancement in cross-priming of antigen-specific T cells in mice receiving Clec9a/OVA TNE. To better harness the immune potentiating effects of iNKT cells with this approach, we incorporated αGalCer adjuvant with antigen into targeted nanoemulsions. While we generally observed rapid maturation of CD8α+ DCs, increased activation of iNKT and NK cells and greater cytokine production with incorporation of αGalCer, we found that enhanced function of CD8+ T cells is dependent on delivery of peptides specifically to Clec9a+ DCs. To highlight the potency and potential of αGalCer as a therapeutic adjuvant, we tested various nanoemulsions against TC-1 tumors, a tumor cell line sensitive to CD8 T cell cytotoxicity. We found that a single dose of targeted nanoemulsion delivering tumor-associated antigen together with αGalCer could control tumor growth in mice, leading to tumor regression. Moreover, we established that therapeutic efficacy correlated to the amount of αGalCer incorporated in the targeted nanoemulsion. Our observations not only highlight the potential use of this targeted nanoemulsion system as a delivery vector for αGalCer to DCs via the Clec9a receptor but also the potency of harnessing iNKT cells in enhancing overall anti-tumor CD8 T cell responses against solid tumors.
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