Co-delivery of the NKT agonist α-galactosylceramide and tumor antigens to cross-priming dendritic cells breaks tolerance to self-antigens and promotes antitumor responses

Vaccines designed to abrogate the tolerance of tumor self-antigens and amplify cytotoxic CD8⁺ T cells (CTLs) have promise for the treatment of cancer. Type I natural killer (NKT) cells have attracted considerable interest in the cancer therapy field. In the current study, we have exploited the unique ability of NKT cells to serve as T-helper cells to license dendritic cells (DCs) for cross priming with the aim to generate efficient CTL antitumor responses. To this end, we designed a nanoparticle-based vaccine to target cross-priming DCs via the Clec9a endocytic pathway. Our results showed for the first time that simultaneous co-delivery of the NKT agonist α-galactosylceramide and tumor self-antigens (Trp2 and gp100) to CD8α⁺ DCs promotes strong antitumor responses in prophylactic and therapeutic settings (advanced solid tumor model in the mouse). We attributed the vaccine's therapeutic effects to NKT cells (but not to T-helper lymphocytes) and CD8⁺ T cells. Efficacy was correlated with an elevated ratio between tumor antigen-specific CD8⁺ T cells and regulatory CD4⁺ T lymphocytes within the tumor. The nanoparticle-based vaccine actively targeted human CLEC9A-expressing BDCA3⁺ DCs - the equivalent of murine cross-priming CD8α⁺ DCs - and induced a strong expansion of effector memory tumor self-antigen (Melan -A)-specific CD8⁺ T cells from peripheral blood mononuclear cells sourced from healthy donors and melanoma patients. Together, our result shed light on novel therapeutic approaches for controlling tumor development.