A robust deep learning platform to predict CD8+ T-cell epitopes

T-cells play a crucial role in the adaptive immune system by inducing an anti-tumour response, defending against pathogens, and maintaining tolerance against self-antigens, which has sparked interest in the development of T-cell-based vaccines and immunotherapies. Because screening antigens driving the T-cell response is currently low-throughput and laborious, computational methods for predicting CD8+ T-cell epitopes have emerged. However, most immunogenicity algorithms struggle to learn features of peptide immunogenicity from small datasets, suffer from HLA bias and are unable to reliably predict pathology-specific CD8+ T-cell epitopes. Therefore, we developed TRAP (T-cell recognition potential of HLA-I presented peptides), a robust deep learning platform for predicting CD8+ T-cell epitopes from MHC-I presented pathogenic and self-peptides. TRAP uses transfer learning, deep learning architecture and MHC binding information to make context-specific predictions of CD8+ T-cell epitopes. TRAP also detects low-confidence predictions for peptides that differ significantly from those in the training datasets to abstain from making incorrect predictions. To estimate the immunogenicity of pathogenic peptides with low-confidence predictions, we further developed a novel metric, RSAT (relative similarity to autoantigens and tumour-associated antigens), as a complementary to ‘dissimilarity to self’ from cancer studies. We used TRAP to identify epitopes from glioblastoma patients as well as SARS-CoV-2 peptides, and it outperformed other algorithms in both cancer and pathogenic settings. Thus, this study presents a novel computational platform for accurately predicting CD8+ T-cell epitopes to foster a better understanding of antigen-specific T-cell response and the development of effective clinical therapeutics. Highlights HLA bias and out-of-distribution problem are causes of poor performance of current state-of-the-art algorithms Transfer learning, deep learning architecture, context-specific and HLA-generalised approaches improve CD8+ T-cell epitope prediction TRAP reports degree of correctness to improve reliability of the prediction A novel metric termed RSAT estimates immunogenicity of pathogenic peptides, as a complementary to ‘dissimilarity to self’ from cancer studies