Titre
In silico and cell-based analyses reveal strong divergence between prediction and observation of T-cell-recognized tumor antigen T-cell epitopes.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Schmidt, J.
Auteure/Auteur
Guillaume, P.
Auteure/Auteur
Dojcinovic, D.
Auteure/Auteur
Karbach, J.
Auteure/Auteur
Coukos, G.
Auteure/Auteur
Luescher, I.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1083-351X
Statut éditorial
Publié
Date de publication
2017-07-14
Volume
292
Numéro
28
Première page
11840
Dernière page/numéro d’article
11849
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Comparative Study ; Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
Tumor exomes provide comprehensive information on mutated, overexpressed genes and aberrant splicing, which can be exploited for personalized cancer immunotherapy. Of particular interest are mutated tumor antigen T-cell epitopes, because neoepitope-specific T cells often are tumoricidal. However, identifying tumor-specific T-cell epitopes is a major challenge. A widely used strategy relies on initial prediction of human leukocyte antigen-binding peptides by in silico algorithms, but the predictive power of this approach is unclear. Here, we used the human tumor antigen NY-ESO-1 (ESO) and the human leukocyte antigen variant HLA-A*0201 (A2) as a model and predicted in silico the 41 highest-affinity, A2-binding 8-11-mer peptides and assessed their binding, kinetic complex stability, and immunogenicity in A2-transgenic mice and on peripheral blood mononuclear cells from ESO-vaccinated melanoma patients. We found that 19 of the peptides strongly bound to A2, 10 of which formed stable A2-peptide complexes and induced CD8(+) T cells in A2-transgenic mice. However, only 5 of the peptides induced cognate T cells in humans; these peptides exhibited strong binding and complex stability and contained multiple large hydrophobic and aromatic amino acids. These results were not predicted by in silico algorithms and provide new clues to improving T-cell epitope identification. In conclusion, our findings indicate that only a small fraction of in silico-predicted A2-binding ESO peptides are immunogenic in humans, namely those that have high peptide-binding strength and complex stability. This observation highlights the need for improving in silico predictions of peptide immunogenicity.
Sujets
PID Serval
serval:BIB_5AC2BD6D841F
PMID
Open Access
Oui
Date de création
2017-06-13T15:53:09.815Z
Date de création dans IRIS
2025-05-20T18:54:16Z