title: Intradermal delivery of TLR agonists in a human explant skin model: preferential activation of migratory dendritic cells by polyribosinic-polyribocytidylic acid and peptidoglycans.
abstract: TLR agonists are attractive candidate adjuvants for therapeutic cancer vaccines as they can induce a balanced humoral and T cell-mediated immune response. With a dense network of dendritic cells (DCs) and draining lymphatics, the skin provides an ideal portal for vaccine delivery. Beside direct DC activation, TLR agonists may also induce DC activation through triggering the release of inflammatory mediators by accessory cells in the skin microenvironment. Therefore, a human skin explant model was used to explore the in vivo potential of intradermally delivered TLR agonists to stimulate Langerhans cells and dermal DCs in their natural complex tissue environment. The skin-emigrated DCs were phenotyped and analyzed for T cell stimulatory capacity. We report that, of six tested TLR-agonists, the TLR2 and -3 agonists peptidoglycan (PGN) and polyribosinic-polyribocytidylic acid (Poly I:C) were uniquely able to enhance the T cell-priming ability of skin-emigrated DCs, which, in the case of PGN, was accompanied by Th1 polarization. The enhanced priming capacity of Poly I:C-stimulated DCs was associated with a strong upregulation of appropriate costimulatory molecules, including CD70, whereas that of PGN-stimulated DCs was associated with the release of a broad array of proinflammatory cytokines. Transcriptional profiling further supported the notion that the PGN- and Poly I:C-induced effects were mediated through binding to TLR2/nucleotide-binding oligomerization domain 2 and TLR3/MDA5, respectively. These data warrant further exploration of PGN and Poly I:C, alone or in combination, as DC-targeted adjuvants for intradermal cancer vaccines.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam 1081 HV, The Netherlands.
authors.forename: Dinja
authors.initials: D
authors.lastname: Oosterhoff
authors.forename: Moniek
authors.initials: M
authors.lastname: Heusinkveld
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Lougheed
authors.forename: Ilona
authors.initials: I
authors.lastname: Kosten
authors.forename: Malin
authors.initials: M
authors.lastname: Lindstedt
authors.forename: Sven C M
authors.initials: SC
authors.lastname: Bruijns
authors.forename: Thomas
authors.initials: T
authors.lastname: van Es
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007271:Injections, Intradermal; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007801:Langerhans Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D010457:Peptidoglycan / Q000008:administration & dosage*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011070:Poly I-C / Q000008:administration & dosage*; D012867:Skin / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008024:Ligands; D010457:Peptidoglycan; D051193:Toll-Like Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D011070:Poly I-C