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. (2nd September 2017)

• Record Type: Journal Article
• Authors: Ghinnagow, Reem; De Meester, Julie; Cruz, Luis Javier; Aspord, Caroline; Corgnac, Stéphanie; Macho-Fernandez, Elodie; Soulard, Daphnée; Fontaine, Josette; Chaperot, Laurence; Charles, Julie; Soncin, Fabrice; Mami-Chouaib, Fathia; Plumas, Joel; Faveeuw, Christelle; Trottein, François
• Is Part Of: Oncoimmunology. Volume 6:Number 9(2017)
• Publication Date: 2017-09-02
• Subjects: Cancer -- dendritic cells -- natural killer T cells -- self antigens -- targeting -- vaccine; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2017.1339855
• Languages: English
• ISSNs: 2162-402X

Abstract

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.