Cancer Immunology, Immunotherapy

, Volume 65, Issue 9, pp 1075–1083 | Cite as

Uptake of synthetic naked RNA by skin-resident dendritic cells via macropinocytosis allows antigen expression and induction of T-cell responses in mice

  • Abderraouf Selmi
  • Fulvia Vascotto
  • Kordula Kautz-Neu
  • Özlem Türeci
  • Ugur Sahin
  • Esther von Stebut
  • Mustafa Diken
  • Sebastian Kreiter
Original Article

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.

Keywords

Naked RNA Intradermal vaccination Macropinocytosis Dermal dendritic cell RNA vaccine Cancer immunotherapy 

Abbreviations

APC

Antigen-presenting cell

DC

Dendritic cell

DT

Diphtheria toxin

DTR

Diphtheria toxin receptor

eGFP

Enhanced green fluorescent protein

HA

Hemagglutinin

IFN

Interferon

LN

Langerin

Luc

Luciferase

SEM

Standard error of mean

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Abderraouf Selmi
    • 1
    • 2
  • Fulvia Vascotto
    • 1
  • Kordula Kautz-Neu
    • 3
  • Özlem Türeci
    • 4
  • Ugur Sahin
    • 1
    • 2
    • 5
  • Esther von Stebut
    • 3
  • Mustafa Diken
    • 1
    • 5
  • Sebastian Kreiter
    • 1
    • 5
  1. 1.TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbHMainzGermany
  2. 2.Research Center for Immunotherapy (FZI)University Medical Center of Johannes Gutenberg UniversityMainzGermany
  3. 3.Department of DermatologyUniversity Medical Center of Johannes Gutenberg UniversityMainzGermany
  4. 4.Cluster for Individualized Immune Intervention (CI3)MainzGermany
  5. 5.BioNTech RNA Pharmaceuticals GmbHMainzGermany

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