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

Hanan Besser,Yoram Louzoun,Sharon Yunger,Efrat Merhavi-Shoham,Cyrille J. Cohen

doi:10.1186/s40425-019-0595-z

Hanan Besser, Yoram Louzoun + Show 3 more

Open Access

https://doi.org/10.1186/s40425-019-0595-z

Copy DOI

Abstract

BackgroundTargeting 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.MethodsHerein, we analyzed several experimental datasets from cancer patients to elaborate better predictive algorithms for T-cell reactivity to neo-epitopes.ResultsIndeed, 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.ConclusionsThe 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.

Highlights

CD8 T cell activation by either exogenous or endogenous epitopes is induced by binding of the T cell receptor to epitopes presented on host MHC class I proteins
Beyond MHC binding, the candidate for affecting T cell response is the number of peptides reaching the Endoplasmic Reticulum (ER). This number determines the number of candidate MHC binding peptides, and in viral responses, we have shown it to be tightly related to the escape mutations [21]
Correlation between neo-antigen features and T cell activation In order to study the factors affecting T cell activation by presented peptides and to develop a classifier for such peptides, we analyzed the response of T-cell cultures derived from eight metastatic melanoma patients and published positive epitopes against sets of predicted-HLA binders as previously described [7]

Summary

Introduction

CD8 T cell activation by either exogenous or endogenous epitopes is induced by binding of the T cell receptor to epitopes presented on host MHC class I proteins. The second class, on which we focus are antigens derived from mutated proteins that could be recognized as foreign, commonly termed “neo-antigens” These antigens have been shown to be relevant in efficient CPI (Check-point inhibitors) treatment and in T-cell based therapies [4]. 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. The response may be affected by the properties of the neo-epitope mutated residues

Methods

Results

Conclusion