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

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License: CC BY 4.0
Serval ID
serval:BIB_7933896A736E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence.
Journal
Frontiers in immunology
Author(s)
Carretero-Iglesia L., Couturaud B., Baumgaertner P., Schmidt J., Maby-El Hajjami H., Speiser D.E., Hebeisen M., Rufer N.
ISSN
1664-3224 (Electronic)
ISSN-L
1664-3224
Publication state
Published
Issued date
2019
Peer-reviewed
Oui
Volume
10
Pages
3016
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
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.
Keywords
CD8 T-cells, CD8 binding dependency, NTAmers, TCR-pMHC binding avidity, functional avidity, melanoma, peptide and CpG-B doses, vaccination
Pubmed
Open Access
Yes
Create date
29/01/2020 17:02
Last modification date
30/04/2021 6:11
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