Type I interferons interfere with the capacity of mRNA lipoplex vaccines to elicit cytolytic T cell responses

Ans De Beuckelaer, Charlotte Pollard, Sandra Van Lint, Kenny Roose, Lien Van Hoecke, Thomas Naessens, Vimal Kumar Udhayakumar, Muriel Smet, Niek Sanders, Stefan Lienenklaus, Xavier Saelens, Siegfried Weiss, Guido Vanham, Johan Grooten, Stefaan De Koker

Research output: Contribution to journalA1: Web of Science-article

Abstract

Given their high potential to evoke cytolytic T cell responses, tumor antigen-encoding messenger RNA (mRNA) vaccines are now being intensively explored as therapeutic cancer vaccines. mRNA vaccines clearly benefit from wrapping the mRNA into nano-sized carriers such as lipoplexes that protect the mRNA from degradation and increase its uptake by dendritic cells in vivo. Nevertheless, the early innate host factors that regulate the induction of cytolytic T cells to mRNA lipoplex vaccines have remained unresolved. Here, we demonstrate that mRNA lipoplexes induce a potent type I interferon (IFN) response upon subcutaneous, intradermal and intranodal injection. Regardless of the route of immunization applied, these type I IFNs interfered with the generation of potent cytolytic T cell responses. Most importantly, blocking type I IFN signaling at the site of immunization through the use of an IFNAR blocking antibody greatly enhanced the prophylactic and therapeutic antitumor efficacy of mRNA lipoplexes in the highly aggressive B16 melanoma model. As type I IFN induction appears to be inherent to the mRNA itself rather than to unique properties of the mRNA lipoplex formulation, preventing type I IFN induction and/or IFNAR signaling at the site of immunization might constitute a widely applicable strategy to improve the potency of mRNA vaccination.

Original languageEnglish
JournalMolecular Therapy
Volume24
Issue number11
Pages (from-to)2012-2020
Number of pages9
ISSN1525-0016
DOIs
Publication statusPublished - 2016

Keywords

  • DENDRITIC CELLS
  • PROSTATE-CANCER
  • IFN-ALPHA
  • VACCINATION
  • ACTIVATION
  • DELIVERY
  • CD8(+)
  • LYMPHOCYTES
  • EFFICACY
  • IMMUNITY

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