title: Type I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses.
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.
authors: Department of Biomedical Molecular Biology, Laboratory Molecular Immunology, Ghent University, Ghent, Belgium.
authors: Ans
authors: A
authors: De Beuckelaer
authors: Department of Biomedical Molecular Biology, Laboratory Molecular Immunology, Ghent University, Ghent, Belgium; Department of Biomedical Sciences, Virology Unit, Institute of Tropical Medicine, Antwerp, Belgium.
authors: Charlotte
authors: C
authors: Pollard
authors: Department of Biochemistry, Cytokine Receptor Lab, Ghent University, Ghent, Belgium; Medical Biotechnology, VIB, Ghent, Belgium.
authors: Sandra
authors: S
authors: Van Lint
authors: Medical Biotechnology, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors: Kenny
authors: K
authors: Roose
authors: Medical Biotechnology, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors: Lien
authors: L
authors: Van Hoecke
authors: Department of Biomedical Molecular Biology, Laboratory Molecular Immunology, Ghent University, Ghent, Belgium.
authors: Thomas
authors: T
authors: Naessens
authors: Department of Biomedical Molecular Biology, Laboratory Molecular Immunology, Ghent University, Ghent, Belgium.
authors: Vimal Kumar
authors: VK
authors: Udhayakumar
authors: Department of Biomedical Molecular Biology, Laboratory Molecular Immunology, Ghent University, Ghent, Belgium.
authors: Muriel
authors: M
authors: Smet
authors: Faculty of Veterinary Medicine, Laboratory of Gene Therapy, Ghent University, Ghent, Belgium.
authors: Niek
authors: N
authors: Sanders
authors: Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany; Centre for Experimental and Clinical Infection Research, Institute for Experimental Infection Research, TWINCORE, Hannover, Germany.
authors: Stefan
authors: S
authors: Lienenklaus
authors: Medical Biotechnology, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors: Xavier
authors: X
authors: Saelens
authors: Institute of Immunology, Medical School Hannover, Hannover, Germany; Department of Molecular Immunology, Helmholtz Centre for infection Research, Braunschweig, Germany.
authors: Siegfried
authors: S
authors: Weiss
authors: Department of Biomedical Sciences, Virology Unit, Institute of Tropical Medicine, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
authors: Guido
authors: G
authors: Vanham
authors: Department of Biomedical Molecular Biology, Laboratory Molecular Immunology, Ghent University, Ghent, Belgium.
authors: Johan
authors: J
authors: Grooten
authors: Department of Biomedical Molecular Biology, Laboratory Molecular Immunology, Ghent University, Ghent, Belgium; Department of Biochemistry, Cytokine Receptor Lab, Ghent University, Ghent, Belgium; Medical Biotechnology, VIB, Ghent, Belgium. Electronic address: stefaan.dekoker@vib-ugent.be.
authors: Stefaan
authors: S
authors: De Koker
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D006801:Humans; D007271:Injections, Intradermal; D007279:Injections, Subcutaneous; D007370:Interferon Type I / Q000378:metabolism*; D008081:Liposomes; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D019496:Cancer Vaccines; D007370:Interferon Type I; D008081:Liposomes; D012333:RNA, Messenger; D053633:Receptor, Interferon alpha-beta