CapHLA: a comprehensive tool to predict peptide presentation and binding to HLA class I and class II

Abstract

Human leukocyte antigen class I (HLA-I) and class II (HLA-II) proteins play an essential role in epitope binding and presentation to initiate an immune response. Accurate prediction of peptide-HLA (pHLA) binding and presentation is critical for developing effective immunotherapies. However, current tools can predict antigens exclusively for pHLA-I or pHLA-II, but not both; have constraints on peptide length; and commonly show unsatisfactory predictive accuracy. Here, we developed a convolution and attention-based model, CapHLA, trained with eluted ligand and binding affinity mass spectrometry data, to predict peptide presentation probability (PB) and binding affinities (BA) for HLA-I and HLA-II. In comparison with 11 other methods, CapHLA consistently showed improved performance in predicting pHLA BA and PB, particularly in HLA-II and non-classical peptide length datasets. Using CapHLA PB and BA predictions in combination with antigen expression level (EP) from transcriptomic data, we developed a neoantigen quality model for predicting immunotherapy response. In analyses of clinical response among 276 cancer patients given immunotherapy and overall survival in 7228 cancer patients, our neoantigen quality model outperformed other genetics-based models in predicting response to checkpoint inhibitors and patient prognosis. This study provides a versatile neoantigen screening tool, illustrating the prognostic value of neoantigen quality.