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Type I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses.
De Beuckelaer, Ans Pollard, Charlotte Van Lint, Sandra Roose, Kenny Van Hoecke, Lien Naessens, Thomas Udhayakumar, Vimal Kumar Smet, Muriel Sanders, Niek Lienenklaus, Stefan
De Beuckelaer, Ans
Pollard, Charlotte
Van Lint, Sandra
Roose, Kenny
Van Hoecke, Lien
Naessens, Thomas
Udhayakumar, Vimal Kumar
Smet, Muriel
Sanders, Niek
Lienenklaus, Stefan
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2016-11
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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.
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Type I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses. 2016, 24 (11):2012-2020 Mol. Ther.
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en
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1525-0024