Type I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621305
Title:
Type I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses.
Authors:
De Beuckelaer, Ans; Pollard, Charlotte; Van Lint, Sandra; Roose, Kenny; Van Hoecke, Lien; Naessens, Thomas; Udhayakumar, Vimal Kumar; Smet, Muriel; Sanders, Niek; Lienenklaus, Stefan; Saelens, Xavier; Weiss, Siegfried; Vanham, Guido; Grooten, Johan; De Koker, Stefaan
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.
Affiliation:
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Type I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses. 2016, 24 (11):2012-2020 Mol. Ther.
Journal:
Molecular therapy : the journal of the American Society of Gene Therapy
Issue Date:
Nov-2016
URI:
http://hdl.handle.net/10033/621305
DOI:
10.1038/mt.2016.161
PubMed ID:
27506450
Type:
Article
Language:
en
ISSN:
1525-0024
Appears in Collections:
publications of the research group molecular Immunology (MOLI); publications of the department experimental Virology([TC]EVIR)

Full metadata record

DC FieldValue Language
dc.contributor.authorDe Beuckelaer, Ansen
dc.contributor.authorPollard, Charlotteen
dc.contributor.authorVan Lint, Sandraen
dc.contributor.authorRoose, Kennyen
dc.contributor.authorVan Hoecke, Lienen
dc.contributor.authorNaessens, Thomasen
dc.contributor.authorUdhayakumar, Vimal Kumaren
dc.contributor.authorSmet, Murielen
dc.contributor.authorSanders, Nieken
dc.contributor.authorLienenklaus, Stefanen
dc.contributor.authorSaelens, Xavieren
dc.contributor.authorWeiss, Siegfrieden
dc.contributor.authorVanham, Guidoen
dc.contributor.authorGrooten, Johanen
dc.contributor.authorDe Koker, Stefaanen
dc.date.accessioned2018-03-06T09:44:42Z-
dc.date.available2018-03-06T09:44:42Z-
dc.date.issued2016-11-
dc.identifier.citationType I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses. 2016, 24 (11):2012-2020 Mol. Ther.en
dc.identifier.issn1525-0024-
dc.identifier.pmid27506450-
dc.identifier.doi10.1038/mt.2016.161-
dc.identifier.urihttp://hdl.handle.net/10033/621305-
dc.description.abstractGiven 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.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshAntibodiesen
dc.subject.meshCancer Vaccinesen
dc.subject.meshHumansen
dc.subject.meshInjections, Intradermalen
dc.subject.meshInjections, Subcutaneousen
dc.subject.meshInterferon Type Ien
dc.subject.meshLiposomesen
dc.subject.meshMelanoma, Experimentalen
dc.subject.meshMiceen
dc.subject.meshRNA, Messengeren
dc.subject.meshReceptor, Interferon alpha-betaen
dc.subject.meshT-Lymphocytes, Cytotoxicen
dc.subject.meshTreatment Outcomeen
dc.titleType I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalMolecular therapy : the journal of the American Society of Gene Therapyen

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