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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

Abstract : 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.
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https://www.hal.inserm.fr/inserm-02436029
Contributor : François Trottein <>
Submitted on : Sunday, January 12, 2020 - 11:21:35 AM
Last modification on : Friday, July 10, 2020 - 5:48:02 PM

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Reem Ghinnagow, Julie de Meester, Luis Javier Cruz, Caroline Aspord, Stephanie Corgnac, et al.. 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. OncoImmunology, Taylor & Francis, 2017, 6 (9), pp.e1339855. ⟨10.1080/2162402X.2017.1339855⟩. ⟨inserm-02436029⟩

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