Deep Neural Networks Predict MHC-I Epitope Presentation and Transfer Learn Neoepitope Immunogenicity

Identifying neoepitopes that elicit an adaptive immune response is a major bottleneck to developing personalized cancer vaccines. Experimental validation of candidate neoepitopes is extremely resource intensive, and the vast majority of candidates are non-immunogenic, making their identification a needle-in-a-haystack problem. To address this challenge, we present computational methods for predicting MHC-I epitopes and identifying immunogenic neoepitopes with improved precision. The BigMHC method comprises an ensemble of seven pan-allelic deep neural networks trained on peptide-MHC eluted ligand data from mass spectrometry assays and transfer learned on data from assays of antigen-specific immune response. Compared with four state-of-the-art classifiers, BigMHC significantly improves the prediction of epitope presentation on a test set of 45,409 MHC ligands among 900,592 random negatives (AUROC=0.9733, AUPRC=0.8779). After transfer learning on immunogenicity data, BigMHC yields significantly higher precision than seven state-of-the-art models in identifying immunogenic neoepitopes, making BigMHC effective in clinical settings. All data and code are freely available at https://github.com/KarchinLab/bigmhc.