Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy
Abstract
Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.
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The vaccination schedule used prevents the typical post-expansion T-cell retraction phase and maintains high frequencies of antigen-specific T cells.
“The schedule was designed to prevent the typical post-expansion T-cell retraction phase and maintain high frequencies of antigen-specific T cells.”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [30]
Their OVA mRNA construct encoded for the H-2Kb-restricted immunodominant epitope OVA 257-264 and the lipid formulation contained DOTAP and DOPE with the mean diameter of mRNA-LNP was 200 nm.
“Their OVA mRNA construct encoded for the H-2Kb-restricted immunodominant epitope OVA 257-264 and the lipid formulation contained DOTAP and DOPE with the mean diameter of mRNA-LNP was 200 nm (30).”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [30]
In the previous study by Kranz et al., a systemic immunization with three doses (40 μg/dose) of mRNA encoding OVA cleared B16-OVA lung metastasis with no tumor at 20 days after the last immunization.
“In the previous study by Kranz et al., a systemic immunization with three doses (40 µg/dose) of mRNA encoding OVA cleared B16-OVA lung metastasis with no tumor at 20 days after the last immunization.”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [30]
It has been demonstrated that mRNA active vaccination can use both the intramuscular as well as the intravenous route (Petsch et al, 2012; Kranz et al, 2016).
“It has been demonstrated that mRNA active vaccination can use both the intramuscular as well as the intravenous route (Petsch et al, 2012; Kranz et al, 2016).”
From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Kranz et al, 2016
Several research groups underlined that the type I interferon response can act as a driving force for mRNA vaccines to elicit cytotoxic T cell responses.
“several research groups underlined that the type I IFN response can act as a driving force for mRNA vaccines to elicit cytotoxic T cell responses [1,60,61]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [60]
Organ selectivity can be achieved by adjusting the proportions of lipid components.
“Organ selectivity can also be achieved by adjusting the proportions of lipid components, for example, to design spleen-targeted mRNA vaccines26,27 or lung-targeted genome editing delivery systems114,134.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [26]
i.v. administration of mRNA vaccines has been shown to induce stronger antigen-specific cytotoxic T cell responses compared with local injection.
“For example, i.v. administration of mRNA vaccines has been shown to induce stronger antigen-specific cytotoxic T cell responses compared with local injection26,148,149.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [26]
In cancer immunotherapy, it is essential to evoke a systemic immune response to obtain antitumor immunity, making i.v. delivery appealing for mRNA-based cancer vaccines.
“In the specific case of cancer immunotherapy, it was proven essential to evoke a systemic immune response to obtain antitumor immunity, which makes i.v.delivery a highly appealing administration route for mRNA-based cancer vaccines [92,136,137].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [92]
The systemic type I IFN response evoked by mRNA LNPs is crucial to activate APCs and effector cells.
“demonstrated that the systemic type I IFN response evoked by mRNA LNPs was crucial to activate APCs and effector cells.”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [92]
Antitumor responses in a lung metastasis model are significantly impaired when tumor-bearing mice are immunized i.v. with mRNA LNPs while receiving i.p. injections with anti-IFNAR1 antibodies.
“Also, antitumor responses in a lung metastasis model were significantly impaired when tumor-bearing mice were immunized i.v. with mRNA LNPs while receiving i.p. injections with anti-IFNAR1 antibodies [92].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [92]
By lowering the lipid-to-mRNA ratio to a lower lipid content, DOTMA-DOPE mRNA LNPs become negatively charged and specifically target DCs in the spleen.
“Interestingly, by lowering the lipid-to-mRNA ratio to a lower lipid content, Kranz et al. demonstrated that DOTMA-DOPE mRNA LNPs become negatively charged and specifically target DCs in the spleen [92,158].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [92]
Two papers showed that intravenous administration of unmodified mRNA lipid nanoparticles triggered a rapid and systemic induction of type I IFNs, involving selective targeting of dendritic cells and macrophages and activation of the TLR7 pathway.
“Two papers showed that the i.v.administration of unmodified mRNA LNPs triggered a rapid and systemic induction of type I IFNs, which involved the selective targeting of DCs and macrophages and the activation of the TLR7 pathway[92,136].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [92]
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- Authors
- Kranz, L. M., Diken, M., Haas, H., Kreiter, S., Loquai, C., Reuter, K. C., Meng, M., Fritz, D., Vascotto, F., Hefesha, H., Grunwitz, C., Vormehr, M., Hüsemann, Y., Selmi, A., Kuhn, A. N., Buck, J., Derhovanessian, E., Rae, R., Attig, S., Diekmann, J., Jabulowsky, R. A., Heesch, S., Hassel, J., Langguth, P., Grabbe, S., Huber, C., Türeci, Ö., & Sahin, U.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- BioNTech (Germany) (DE)
- University Hospital Heidelberg (DE)
- ORCID
- Venue
- Nature
- Published
- 2016-06
- Volume
- 534
- Issue
- 7607
- Pages
- 396-401
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2412158473
- Cited by
- 1,771
- References
- 52
- Citations by year
- 2026: 139 · 2025: 209 · 2024: 210 · 2023: 210 · 2022: 213 · 2021: 209 · 2020: 172 · 2019: 129 · 2018: 122 · 2017: 125 · 2016: 26 · 2015: 2
- FWCI
- 67.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- dendritic cell targeting, interferon-alpha, cancer immunotherapy, melanoma, plasmacytoid dendritic cells, macrophages, type I interferon, antigen-specific T cell responses, neoantigens, autoantigens, tumor rejection
- MeSH terms
- Animals, Antigens, Neoplasm, Antigens, Viral, Autoantigens, Dendritic Cells, Disease Models, Animal, Drug Carriers, Female, Humans, Immunotherapy, Interferon Type I, Lymphocyte Activation, Lymphoid Tissue, Macrophages, Male, Melanoma, Membrane Glycoproteins, Mice, Inbred C57BL, RNA, T-Lymphocytes, Clinical Trials, Phase I as Topic, Antigen Presentation, Cancer Vaccines, Toll-Like Receptor 7, Mice, Nanoparticles, Static Electricity, Administration, Intravenous
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