Cargando…

High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence

CD8 T-cell response efficiency critically depends on the TCR binding strength to peptide-MHC, i.e., the TCR binding avidity. A current challenge in onco-immunology lies in the evaluation of vaccine protocols selecting for tumor-specific T-cells of highest avidity, offering maximal immune protection...

Descripción completa

Detalles Bibliográficos
Autores principales: Carretero-Iglesia, Laura, Couturaud, Barbara, Baumgaertner, Petra, Schmidt, Julien, Maby-El Hajjami, Hélène, Speiser, Daniel E., Hebeisen, Michael, Rufer, Nathalie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960191/
https://www.ncbi.nlm.nih.gov/pubmed/31969886
http://dx.doi.org/10.3389/fimmu.2019.03016
_version_ 1783487739269742592
author Carretero-Iglesia, Laura
Couturaud, Barbara
Baumgaertner, Petra
Schmidt, Julien
Maby-El Hajjami, Hélène
Speiser, Daniel E.
Hebeisen, Michael
Rufer, Nathalie
author_facet Carretero-Iglesia, Laura
Couturaud, Barbara
Baumgaertner, Petra
Schmidt, Julien
Maby-El Hajjami, Hélène
Speiser, Daniel E.
Hebeisen, Michael
Rufer, Nathalie
author_sort Carretero-Iglesia, Laura
collection PubMed
description CD8 T-cell response efficiency critically depends on the TCR binding strength to peptide-MHC, i.e., the TCR binding avidity. A current challenge in onco-immunology lies in the evaluation of vaccine protocols selecting for tumor-specific T-cells of highest avidity, offering maximal immune protection against tumor cells and clinical benefit. Here, we investigated the impact of peptide and CpG/adjuvant doses on the quality of vaccine-induced CD8 T-cells in relation to binding avidity and functional responses in treated melanoma patients. Using TCR-pMHC binding avidity measurements combined to phenotype and functional assays, we performed a comprehensive study on representative tumor antigen-specific CD8 T-cell clones (n = 454) from seven patients vaccinated with different doses of Melan-A/ELA peptide (0.1 mg vs. 0.5 mg) and CpG-B adjuvant (1–1.3 mg vs. 2.6 mg). Vaccination with high peptide dose favored the early and strong in vivo expansion and differentiation of Melan-A-specific CD8 T-cells. Consistently, T-cell clones generated from those patients showed increased TCR binding avidity (i.e., slow off-rates and CD8 binding independency) readily after 4 monthly vaccine injections (4v). In contrast, the use of low peptide or high CpG-B doses required 8 monthly vaccine injections (8v) for the enrichment of anti-tumor T-cells with high TCR binding avidity and low CD8 binding dependency. Importantly, the CD8 binding-independent vaccine-induced CD8 T-cells displayed enhanced functional avidity, reaching a plateau of maximal function. Thus, T-cell functional potency following peptide/CpG/IFA vaccination may not be further improved beyond a certain TCR binding avidity limit. Our results also indicate that while high peptide dose vaccination induced the early selection of Melan-A-specific CD8 T-cells of increased functional competence, continued serial vaccinations also promoted such high-avidity T-cells. Overall, the systematic assessment of T-cell binding avidity may contribute to optimize vaccine design for improving clinical efficacy.
format Online
Article
Text
id pubmed-6960191
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-69601912020-01-22 High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence Carretero-Iglesia, Laura Couturaud, Barbara Baumgaertner, Petra Schmidt, Julien Maby-El Hajjami, Hélène Speiser, Daniel E. Hebeisen, Michael Rufer, Nathalie Front Immunol Immunology CD8 T-cell response efficiency critically depends on the TCR binding strength to peptide-MHC, i.e., the TCR binding avidity. A current challenge in onco-immunology lies in the evaluation of vaccine protocols selecting for tumor-specific T-cells of highest avidity, offering maximal immune protection against tumor cells and clinical benefit. Here, we investigated the impact of peptide and CpG/adjuvant doses on the quality of vaccine-induced CD8 T-cells in relation to binding avidity and functional responses in treated melanoma patients. Using TCR-pMHC binding avidity measurements combined to phenotype and functional assays, we performed a comprehensive study on representative tumor antigen-specific CD8 T-cell clones (n = 454) from seven patients vaccinated with different doses of Melan-A/ELA peptide (0.1 mg vs. 0.5 mg) and CpG-B adjuvant (1–1.3 mg vs. 2.6 mg). Vaccination with high peptide dose favored the early and strong in vivo expansion and differentiation of Melan-A-specific CD8 T-cells. Consistently, T-cell clones generated from those patients showed increased TCR binding avidity (i.e., slow off-rates and CD8 binding independency) readily after 4 monthly vaccine injections (4v). In contrast, the use of low peptide or high CpG-B doses required 8 monthly vaccine injections (8v) for the enrichment of anti-tumor T-cells with high TCR binding avidity and low CD8 binding dependency. Importantly, the CD8 binding-independent vaccine-induced CD8 T-cells displayed enhanced functional avidity, reaching a plateau of maximal function. Thus, T-cell functional potency following peptide/CpG/IFA vaccination may not be further improved beyond a certain TCR binding avidity limit. Our results also indicate that while high peptide dose vaccination induced the early selection of Melan-A-specific CD8 T-cells of increased functional competence, continued serial vaccinations also promoted such high-avidity T-cells. Overall, the systematic assessment of T-cell binding avidity may contribute to optimize vaccine design for improving clinical efficacy. Frontiers Media S.A. 2020-01-08 /pmc/articles/PMC6960191/ /pubmed/31969886 http://dx.doi.org/10.3389/fimmu.2019.03016 Text en Copyright © 2020 Carretero-Iglesia, Couturaud, Baumgaertner, Schmidt, Maby-El Hajjami, Speiser, Hebeisen and Rufer. http://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
Carretero-Iglesia, Laura
Couturaud, Barbara
Baumgaertner, Petra
Schmidt, Julien
Maby-El Hajjami, Hélène
Speiser, Daniel E.
Hebeisen, Michael
Rufer, Nathalie
High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence
title High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence
title_full High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence
title_fullStr High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence
title_full_unstemmed High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence
title_short High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence
title_sort high peptide dose vaccination promotes the early selection of tumor antigen-specific cd8 t-cells of enhanced functional competence
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960191/
https://www.ncbi.nlm.nih.gov/pubmed/31969886
http://dx.doi.org/10.3389/fimmu.2019.03016
work_keys_str_mv AT carreteroiglesialaura highpeptidedosevaccinationpromotestheearlyselectionoftumorantigenspecificcd8tcellsofenhancedfunctionalcompetence
AT couturaudbarbara highpeptidedosevaccinationpromotestheearlyselectionoftumorantigenspecificcd8tcellsofenhancedfunctionalcompetence
AT baumgaertnerpetra highpeptidedosevaccinationpromotestheearlyselectionoftumorantigenspecificcd8tcellsofenhancedfunctionalcompetence
AT schmidtjulien highpeptidedosevaccinationpromotestheearlyselectionoftumorantigenspecificcd8tcellsofenhancedfunctionalcompetence
AT mabyelhajjamihelene highpeptidedosevaccinationpromotestheearlyselectionoftumorantigenspecificcd8tcellsofenhancedfunctionalcompetence
AT speiserdaniele highpeptidedosevaccinationpromotestheearlyselectionoftumorantigenspecificcd8tcellsofenhancedfunctionalcompetence
AT hebeisenmichael highpeptidedosevaccinationpromotestheearlyselectionoftumorantigenspecificcd8tcellsofenhancedfunctionalcompetence
AT rufernathalie highpeptidedosevaccinationpromotestheearlyselectionoftumorantigenspecificcd8tcellsofenhancedfunctionalcompetence