Type I interferons interfere with the capacity of mRNA lipoplex vaccines to elicit cytolytic T cell responses
Open accessAbstract
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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These alterations possibly lead to a blunted specific immune response.
“These alterations possibly lead to a blunted specific immune response.37,133, 134, 135”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [133]
The efficacy to evoke CTL antitumor immune responses in a B16 melanoma model of s.c. or i.d. administered DOTAP-DOPE mRNA LNPs is strongly increased after type I IFN blockade.
“De Beuckelaer and colleagues demonstrated that the efficacy to evoke (CTL) antitumor immune responses in a B16 melanoma model of s.c. or i.d.administered DOTAP-DOPE mRNA LNPs, was strongly increased after type I IFN blockade [165].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [165]
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- Authors
- De Beuckelaer, A., Pollard, C., Van Lint, S., Roose, K., Van Hoecke, L., Naessens, T., Udhayakumar, V. K., Smet, M., Sanders, N., Lienenklaus, S., Saelens, X., Weiss, S., Vanham, G., Grooten, J., & De Koker, S.
- Affiliations
- Ghent University (BE)
- Vlaams Instituut voor Biotechnologie (BE)
- Medizinische Hochschule Hannover (DE)
- University of Antwerp (BE)
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 24
- Issue
- 11
- Pages
- 2012-2020
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC5154477
- OpenAlex
- W2484775100
- Cited by
- 122
- References
- 36
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 16 · 2023: 8 · 2022: 25 · 2021: 26 · 2020: 10 · 2019: 11 · 2018: 4 · 2017: 6
- FWCI
- 4.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- HZI (Helmholtz Centre for Infection Research) (submittedVersion, cc-by-nc-sa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Agentschap voor Innovatie door Wetenschap en Technologie
- Vlaamse regering (BOF09/01M00709)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- type I interferon, IFNAR signaling, cancer vaccines, B16 melanoma, dendritic cell uptake, route of immunization, antitumor immunity
- MeSH terms
- Animals, Antibodies, Humans, Injections, Intradermal, Injections, Subcutaneous, Interferon Type I, Liposomes, Melanoma, Experimental, RNA, Messenger, T-Lymphocytes, Cytotoxic, Treatment Outcome, Cancer Vaccines, Mice, Receptor, Interferon alpha-beta
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