Cargando…

Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides

BACKGROUND: Targeting epitopes derived from neo-antigens (or “neo-epitopes”) represents a promising immunotherapy approach with limited off-target effects. However, most peptides predicted using MHC binding prediction algorithms do not induce a CD8 + T cell response, and there is a crucial need to r...

Descripción completa

Detalles Bibliográficos
Autores principales: Besser, Hanan, Yunger, Sharon, Merhavi-Shoham, Efrat, Cohen, Cyrille J., Louzoun, Yoram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532181/
https://www.ncbi.nlm.nih.gov/pubmed/31118084
http://dx.doi.org/10.1186/s40425-019-0595-z
_version_ 1783420964536582144
author Besser, Hanan
Yunger, Sharon
Merhavi-Shoham, Efrat
Cohen, Cyrille J.
Louzoun, Yoram
author_facet Besser, Hanan
Yunger, Sharon
Merhavi-Shoham, Efrat
Cohen, Cyrille J.
Louzoun, Yoram
author_sort Besser, Hanan
collection PubMed
description BACKGROUND: Targeting epitopes derived from neo-antigens (or “neo-epitopes”) represents a promising immunotherapy approach with limited off-target effects. However, most peptides predicted using MHC binding prediction algorithms do not induce a CD8 + T cell response, and there is a crucial need to refine the predictions to readily identify the best antigens that could mediate T-cell responses. Such a response requires a high enough number of epitopes bound to the target MHC. This number is correlated with both the peptide-MHC binding affinity and the number of peptides reaching the ER. Beyond this, the response may be affected by the properties of the neo-epitope mutated residues. METHODS: Herein, we analyzed several experimental datasets from cancer patients to elaborate better predictive algorithms for T-cell reactivity to neo-epitopes. RESULTS: Indeed, potent classifiers for epitopes derived from neo-antigens in melanoma and other tumors can be developed based on biochemical properties of the mutated residue, the antigen expression level and the peptide processing stage. Among MHC binding peptides, the present classifiers can remove half of the peptides falsely predicted to activate T cells while maintaining the absolute majority of reactive peptides. CONCLUSIONS: The classifier properties further highlight the contribution of the quantity of peptides reaching the ER and the mutation type to CD8 + T cell responses. These classifiers were then validated on neo-antigens obtained from other datasets, confirming the validity of our prediction. Algorithm Availability: http://peptibase.cs.biu.ac.il/Tcell_predictor/ or by request from the authors as a standalone code.
format Online
Article
Text
id pubmed-6532181
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-65321812019-05-28 Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides Besser, Hanan Yunger, Sharon Merhavi-Shoham, Efrat Cohen, Cyrille J. Louzoun, Yoram J Immunother Cancer Research Article BACKGROUND: Targeting epitopes derived from neo-antigens (or “neo-epitopes”) represents a promising immunotherapy approach with limited off-target effects. However, most peptides predicted using MHC binding prediction algorithms do not induce a CD8 + T cell response, and there is a crucial need to refine the predictions to readily identify the best antigens that could mediate T-cell responses. Such a response requires a high enough number of epitopes bound to the target MHC. This number is correlated with both the peptide-MHC binding affinity and the number of peptides reaching the ER. Beyond this, the response may be affected by the properties of the neo-epitope mutated residues. METHODS: Herein, we analyzed several experimental datasets from cancer patients to elaborate better predictive algorithms for T-cell reactivity to neo-epitopes. RESULTS: Indeed, potent classifiers for epitopes derived from neo-antigens in melanoma and other tumors can be developed based on biochemical properties of the mutated residue, the antigen expression level and the peptide processing stage. Among MHC binding peptides, the present classifiers can remove half of the peptides falsely predicted to activate T cells while maintaining the absolute majority of reactive peptides. CONCLUSIONS: The classifier properties further highlight the contribution of the quantity of peptides reaching the ER and the mutation type to CD8 + T cell responses. These classifiers were then validated on neo-antigens obtained from other datasets, confirming the validity of our prediction. Algorithm Availability: http://peptibase.cs.biu.ac.il/Tcell_predictor/ or by request from the authors as a standalone code. BioMed Central 2019-05-22 /pmc/articles/PMC6532181/ /pubmed/31118084 http://dx.doi.org/10.1186/s40425-019-0595-z Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Besser, Hanan
Yunger, Sharon
Merhavi-Shoham, Efrat
Cohen, Cyrille J.
Louzoun, Yoram
Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides
title Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides
title_full Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides
title_fullStr Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides
title_full_unstemmed Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides
title_short Level of neo-epitope predecessor and mutation type determine T cell activation of MHC binding peptides
title_sort level of neo-epitope predecessor and mutation type determine t cell activation of mhc binding peptides
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532181/
https://www.ncbi.nlm.nih.gov/pubmed/31118084
http://dx.doi.org/10.1186/s40425-019-0595-z
work_keys_str_mv AT besserhanan levelofneoepitopepredecessorandmutationtypedeterminetcellactivationofmhcbindingpeptides
AT yungersharon levelofneoepitopepredecessorandmutationtypedeterminetcellactivationofmhcbindingpeptides
AT merhavishohamefrat levelofneoepitopepredecessorandmutationtypedeterminetcellactivationofmhcbindingpeptides
AT cohencyrillej levelofneoepitopepredecessorandmutationtypedeterminetcellactivationofmhcbindingpeptides
AT louzounyoram levelofneoepitopepredecessorandmutationtypedeterminetcellactivationofmhcbindingpeptides