title: TLR-3 stimulation improves anti-tumor immunity elicited by dendritic cell exosome-based vaccines in a murine model of melanoma.
abstract: Dendritic cell (DC)-derived exosomes (Dexo) contain the machinery necessary to activate potent antigen-specific immune responses. As promising cell-free immunogens, Dexo have been tested in previous clinical trials for cancer vaccine immunotherapy, yet resulted in limited therapeutic benefit. Here, we explore a novel Dexo vaccine formulation composed of Dexo purified from DCs loaded with antigens and matured with either the TLR-3 ligand poly(I:C), the TLR-4 ligand LPS or the TLR-9 ligand CpG-B. When poly(I:C) was used to produce exosomes together with ovalbumin (OVA), the resulting Dexo vaccine strongly stimulated OVA-specific CD8(+) and CD4(+) T cells to proliferate and acquire effector functions. When a B16F10 melanoma cell lysate was used to load DCs with tumor antigens during exosome production together with poly(I:C), we obtained a Dexo vaccine capable of inducing robust activation of melanoma-specific CD8(+) T cells and the recruitment of cytotoxic CD8(+) T cells, NK and NK-T cells to the tumor site, resulting in significantly reduced tumor growth and enhanced survival as compared to a Dexo vaccine formulation similar to the one previously tested on human patients. Our results indicate that poly(I:C) is a particularly favorable TLR agonist for DC maturation during antigen loading and exosome production for cancer immunotherapy.
authors.affiliation: Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Damo
authors.affiliation: Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: David S
authors.initials: DS
authors.lastname: Wilson
authors.affiliation: Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale Lausanne, CH-1015 Lausanne, Switzerland.|Center of PhenoGenomics, School of Life Sciences, Ecole Polytechnique Fédérale Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Simeoni
authors.affiliation: Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale Lausanne, CH-1015 Lausanne, Switzerland.|Institute for Chemical Science and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale Lausanne, CH-1015 Lausanne, Switzerland.|Institute for Molecular Engineering, University of Chicago, IL 60637, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D055354:Exosomes / Q000276:immunology; D005260:Female; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D008070:Lipopolysaccharides; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D010047:Ovalbumin