Description

Induction of tumor-specific CD8⁺ T cell responses through nanoparticle-mediated delivery of tumor self Ag and a-galactosylceramide to mouse and human dendritic cells

Ghinnagow R¹, Asport C², De Meester J¹, Javier Cruz L³ , Macho-Fernandez E¹, Soncin F⁴, Pluma J², Faveeuw F¹ and Trottein F^1*

¹CIIL-Inserm U1019-CNRS UMR8204-Université Lille-Institut Pasteur de Lille France; ^2|Etablissement Français du Sang, Grenoble, France; ³Leiden University Medical Center, Leiden, The Netherlands.⁴IBL, CNRS UMR8161-Institut Pasteur de Lille, France

*corresponding author

Nanotechnology-based delivery of tumor antigens (Ags) may be promising for cancer immunotherapy due to its dose sparing and prolonged/continuous Ag presentation feature. Moreover, recent studies have emphasized the added-value of using nanoparticulate delivery systems for active targeting of dendritic cells (DCs). We herein describe the effect of a nanoparticle-based vaccine on the development of specific non-self-Ag and self-Ag CD8⁺ T cells and on the control of solid tumor progression in the mouse system. Incorporation of a-galactosylceramide (a-GalCer), a superagonist of invariant natural killer T cells (iNKT), used here as an adjuvant, and tumor Ags into PLGA-based nanoparticulates decorated with anti-clec9a antibodies leads to a strong primary and secondary activation of iNKT cells and to the expansion of cytotoxic CD8⁺ T cells. Prophylactic and therapeutic benefit of such vaccine on antitumor CD8⁺ T cell responses was observed in a model of subcutaneous lymphoma and melanoma. Nanoparticles armed with anti-CLEC9a antibodies target human BDCA3⁺ DC-the equivalent of mouse CD8a⁺ DCs-and trigger strong iNKT cell response in term of cytokine production. Finally, we report that active co-delivery of a-GalCer and the self-antigen melan A promotes the expansion of human antigen-specific CD8⁺ T cells in vitro. These data highlight the potential benefit of delivering tumor Ag and a-GalCer into cross-presenting DCs to improve vaccine-based tumour immunotherapy.

Supported by the Institut National du Cancer (PLBIO13-241-2013-111)