Optimized Epitope-Flanking Sequences Enhance Antigen Presentation and T-Cell Responses Following mRNA Vaccination.
6 affiliations
- 1Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada.
- 2Epitopea, Inc., Montréal, QC H3T 1J4, Canada.
- 3Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada.
- 4Cognate Biotechnology Research, Montréal, QC H2S 3H1, Canada.
- 5Department of Chemistry, Université de Montréal, Montréal, QC H2V 0B3, Canada.
- 6Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
Abstract
mRNA vaccines can encode multiple tumor antigens whose presentation ultimately depends on adequate intracellular processing. To evaluate the potential impact of epitope-flanking sequences, we compared the immunogenicity of two mRNA vaccines in the MC38 mouse model. Both vaccines coded for the same tumor-specific antigens (TSAs). The only difference between the two vaccines was the identity of the epitope-flanking amino acids. The vaccine encoding TSAs bordered by optimized flanking sequences (TSA-Opti) cleared established tumors and elicited robust CD8⁺ T-cell responses. In contrast, the vaccine encoding the same TSAs surrounded by natural flanking sequences (TSA-Nat) induced weaker responses and incomplete protection against tumor growth. Quantitative immunopeptidomics showed that TSA-Opti increased antigen presentation levels, providing a mechanistic link between flanking-sequence design and the enhanced magnitude, clonal diversity, and functionality of TSA-specific CD8+ T cells. TSA-Opti further promoted durable memory, conferring long-term protection against tumor rechallenge. These results identify epitope-flanking sequences as tunable design elements that control peptide-MHC I density and thereby shape the magnitude, clonal diversity, tissue localization, and durability of antitumor CD8⁺ T-cell immunity.
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BibTeX
@article{hardy2026optimized,
title = {{Optimized Epitope-Flanking Sequences Enhance Antigen Presentation and T-Cell Responses Following mRNA Vaccination.}},
author = {Marie-Pierre Hardy and Gabriel Ouellet-Lavallée and Catherine Thériault and Chantal Durette and Krystel Vincent and Robin Minati and Isabelle Caron and Assya Trofimov and Joel Lanoix and Jean-Philippe Laverdure and Pierre Thibault and Claude Perreault},
journal = {Cells},
year = {2026},
month = sep,
doi = {10.3390/cells15191753},
url = {https://europepmc.org/article/MED/42882451},
note = {CC BY},
}
RIS
TY - JOUR
TI - Optimized Epitope-Flanking Sequences Enhance Antigen Presentation and T-Cell Responses Following mRNA Vaccination.
AU - Marie-Pierre Hardy
AU - Gabriel Ouellet-Lavallée
AU - Catherine Thériault
AU - Chantal Durette
AU - Krystel Vincent
AU - Robin Minati
AU - Isabelle Caron
AU - Assya Trofimov
AU - Joel Lanoix
AU - Jean-Philippe Laverdure
AU - Pierre Thibault
AU - Claude Perreault
PY - 2026
DA - 2026/09/26
JO - Cells
DO - 10.3390/cells15191753
UR - https://europepmc.org/article/MED/42882451
AB - mRNA vaccines can encode multiple tumor antigens whose presentation ultimately depends on adequate intracellular processing. To evaluate the potential impact of epitope-flanking sequences, we compared the immunogenicity of two mRNA vaccines in the MC38 mouse model. Both vaccines coded for the same tumor-specific antigens (TSAs). The only difference between the two vaccines was the identity of the epitope-flanking amino acids. The vaccine encoding TSAs bordered by optimized flanking sequences (TSA-Opti) cleared established tumors and elicited robust CD8⁺ T-cell responses. In contrast, the vaccine encoding the same TSAs surrounded by natural flanking sequences (TSA-Nat) induced weaker responses and incomplete protection against tumor growth. Quantitative immunopeptidomics showed that TSA-Opti increased antigen presentation levels, providing a mechanistic link between flanking-sequence design and the enhanced magnitude, clonal diversity, and functionality of TSA-specific CD8+ T cells. TSA-Opti further promoted durable memory, conferring long-term protection against tumor rechallenge. These results identify epitope-flanking sequences as tunable design elements that control peptide-MHC I density and thereby shape the magnitude, clonal diversity, tissue localization, and durability of antitumor CD8⁺ T-cell immunity.
SN - 2073-4409
ER -