title: Uptake of synthetic naked RNA by skin-resident dendritic cells via macropinocytosis allows antigen expression and induction of T-cell responses in mice.
abstract: Intradermal administration of antigen-encoding RNA has entered clinical testing for cancer vaccination. However, insight into the underlying mechanism of RNA uptake, translation and antigen presentation is still limited. Utilizing pharmacologically optimized naked RNA, the dose-response kinetics revealed a rise in reporter signal with increasing RNA amounts and a prolonged RNA translation of reporter protein up to 30 days after intradermal injection. Dendritic cells (DCs) in the dermis were shown to engulf RNA, and the signal arising from the reporter RNA was significantly diminished after DC depletion. Macropinocytosis was relevant for intradermal RNA uptake and translation in vitro and in vivo. By combining intradermal RNA vaccination and inhibition of macropinocytosis, we show that effective priming of antigen-specific CD8(+) T-cells also relies on this uptake mechanism. This report demonstrates that direct antigen translation by dermal DCs after intradermal naked RNA vaccination is relevant for efficient priming of antigen-specific T-cells.
authors.affiliation: TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, Freiligrathstraße 12, 55131, Mainz, Germany.|Research Center for Immunotherapy (FZI), University Medical Center of Johannes Gutenberg University, Mainz, Germany.
authors.forename: Abderraouf
authors.initials: A
authors.lastname: Selmi
authors.affiliation: TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, Freiligrathstraße 12, 55131, Mainz, Germany.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Vascotto
authors.affiliation: Department of Dermatology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
authors.forename: Kordula
authors.initials: K
authors.lastname: Kautz-Neu
authors.affiliation: Cluster for Individualized Immune Intervention (CI3), Mainz, Germany.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Türeci
authors.affiliation: TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, Freiligrathstraße 12, 55131, Mainz, Germany.|Research Center for Immunotherapy (FZI), University Medical Center of Johannes Gutenberg University, Mainz, Germany.|BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.affiliation: Department of Dermatology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: von Stebut
authors.affiliation: TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, Freiligrathstraße 12, 55131, Mainz, Germany. Mustafa.Diken@TrOn-Mainz.de.|BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany. Mustafa.Diken@TrOn-Mainz.de.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Diken
authors.affiliation: TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, Freiligrathstraße 12, 55131, Mainz, Germany. Sebastian.Kreiter@TrOn-Mainz.de.|BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany. Sebastian.Kreiter@TrOn-Mainz.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kreiter
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007271:Injections, Intradermal; D051379:Mice; D008810:Mice, Inbred C57BL; D010873:Pinocytosis; D012313:RNA / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D012313:RNA
keywords: Cancer immunotherapy; Dermal dendritic cell; Intradermal vaccination; Macropinocytosis; Naked RNA; RNA vaccine