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

Journal for ImmunoTherapy of Cancer

Sharon Yunger¹  Efrat Merhavi-Shoham¹  Cyrille J. Cohen²  Hanan Besser³  Yoram Louzoun³ 

[1] 0000 0001 2107 2845, grid.413795.d, Ella Lemelbaum Institute for Immuno Oncology, Sheba Medical Center, Ramat Gan, Israel;0000 0004 1937 0503, grid.22098.31, Laboratory of Tumor Immunology and Immunotherapy, Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel;0000 0004 1937 0503, grid.22098.31, The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, 5290002, Ramat Gan, Israel;0000 0004 1937 0503, grid.22098.31, Department of Mathematics, Bar-Ilan University, 5290002, Ramat Gan, Israel;

关键词: T cell activation;    Machine Learning;    Neoantigen;    MHC-binding peptides;   

DOI  :  10.1186/s40425-019-0595-z

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY