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mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model
An mRNA with unmodified nucleosides induces type I interferons (IFN-I) through the stimulation of innate immune sensors. Whether IFN-I induced by mRNA vaccine is crucial for anti-tumor immune response remains to be elucidated. In this study, we investigated the immunogenicity and anti-tumor response...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9614103/ https://www.ncbi.nlm.nih.gov/pubmed/36311701 http://dx.doi.org/10.3389/fimmu.2022.983000 |
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author | Sittplangkoon, Chutamath Alameh, Mohamad-Gabriel Weissman, Drew Lin, Paulo J. C. Tam, Ying K. Prompetchara, Eakachai Palaga, Tanapat |
author_facet | Sittplangkoon, Chutamath Alameh, Mohamad-Gabriel Weissman, Drew Lin, Paulo J. C. Tam, Ying K. Prompetchara, Eakachai Palaga, Tanapat |
author_sort | Sittplangkoon, Chutamath |
collection | PubMed |
description | An mRNA with unmodified nucleosides induces type I interferons (IFN-I) through the stimulation of innate immune sensors. Whether IFN-I induced by mRNA vaccine is crucial for anti-tumor immune response remains to be elucidated. In this study, we investigated the immunogenicity and anti-tumor responses of mRNA encoding tumor antigens with different degrees of N1-methylpseudouridine (m1Ψ) modification in B16 melanoma model. Our results demonstrated that ovalbumin (OVA) encoding mRNA formulated in a lipid nanoparticle (OVA-LNP) induced substantial IFN-I production and the maturation of dendritic cells (DCs) with negative correlation with increasing percentages of m1Ψ modification. In B16-OVA murine melanoma model, unmodified OVA-LNP significantly reduced tumor growth and prolonged survival, compared to OVA-LNP with m1Ψ modification. This robust anti-tumor effect correlated with the increase in intratumoral CD40(+) DCs and the frequency of granzyme B(+)/IFN-γ(+)/TNF-α(+) polyfunctional OVA peptide-specific CD8(+) T cells. Blocking type I IFN receptor completely reversed the anti-tumor immunity of unmodified mRNA-OVA reflected in a significant decrease in OVA-specific IFN-γ secreting T cells and enrichment of PD-1(+) tumor-infiltrating T cells. The robust anti-tumor effect of unmodified OVA-LNP was also observed in the lung metastatic tumor model. Finally, this mRNA vaccine was tested using B16 melanoma neoantigens (Pbk-Actn4) which resulted in delayed tumor growth. Taken together, our findings demonstrated that an unmodified mRNA vaccine induces IFN-I production or the downstream signaling cascades which plays a crucial role in inducing robust anti-tumor T cell response for controlling tumor growth and metastasis. |
format | Online Article Text |
id | pubmed-9614103 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96141032022-10-29 mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model Sittplangkoon, Chutamath Alameh, Mohamad-Gabriel Weissman, Drew Lin, Paulo J. C. Tam, Ying K. Prompetchara, Eakachai Palaga, Tanapat Front Immunol Immunology An mRNA with unmodified nucleosides induces type I interferons (IFN-I) through the stimulation of innate immune sensors. Whether IFN-I induced by mRNA vaccine is crucial for anti-tumor immune response remains to be elucidated. In this study, we investigated the immunogenicity and anti-tumor responses of mRNA encoding tumor antigens with different degrees of N1-methylpseudouridine (m1Ψ) modification in B16 melanoma model. Our results demonstrated that ovalbumin (OVA) encoding mRNA formulated in a lipid nanoparticle (OVA-LNP) induced substantial IFN-I production and the maturation of dendritic cells (DCs) with negative correlation with increasing percentages of m1Ψ modification. In B16-OVA murine melanoma model, unmodified OVA-LNP significantly reduced tumor growth and prolonged survival, compared to OVA-LNP with m1Ψ modification. This robust anti-tumor effect correlated with the increase in intratumoral CD40(+) DCs and the frequency of granzyme B(+)/IFN-γ(+)/TNF-α(+) polyfunctional OVA peptide-specific CD8(+) T cells. Blocking type I IFN receptor completely reversed the anti-tumor immunity of unmodified mRNA-OVA reflected in a significant decrease in OVA-specific IFN-γ secreting T cells and enrichment of PD-1(+) tumor-infiltrating T cells. The robust anti-tumor effect of unmodified OVA-LNP was also observed in the lung metastatic tumor model. Finally, this mRNA vaccine was tested using B16 melanoma neoantigens (Pbk-Actn4) which resulted in delayed tumor growth. Taken together, our findings demonstrated that an unmodified mRNA vaccine induces IFN-I production or the downstream signaling cascades which plays a crucial role in inducing robust anti-tumor T cell response for controlling tumor growth and metastasis. Frontiers Media S.A. 2022-10-14 /pmc/articles/PMC9614103/ /pubmed/36311701 http://dx.doi.org/10.3389/fimmu.2022.983000 Text en Copyright © 2022 Sittplangkoon, Alameh, Weissman, Lin, Tam, Prompetchara and Palaga https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Sittplangkoon, Chutamath Alameh, Mohamad-Gabriel Weissman, Drew Lin, Paulo J. C. Tam, Ying K. Prompetchara, Eakachai Palaga, Tanapat mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model |
title | mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model |
title_full | mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model |
title_fullStr | mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model |
title_full_unstemmed | mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model |
title_short | mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model |
title_sort | mrna vaccine with unmodified uridine induces robust type i interferon-dependent anti-tumor immunity in a melanoma model |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9614103/ https://www.ncbi.nlm.nih.gov/pubmed/36311701 http://dx.doi.org/10.3389/fimmu.2022.983000 |
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