Neural network models for sequence-based TCR and HLA association prediction.

T cells rely on their T cell receptors (TCRs) to discern foreign antigens presented by human leukocyte antigen (HLA) proteins. The TCRs of an individual contain a record of this individual's past immune activities, such as immune response to infections or vaccines. Mining the TCR data may recover useful information or biomarkers for immune related diseases or conditions. Some TCRs are observed only in the individuals with certain HLA alleles, and thus characterizing TCRs requires a thorough understanding of TCR-HLA associations. The extensive diversity of HLA alleles and the rareness of some HLA alleles present a formidable challenge for this task. Existing methods either treat HLA as a categorical variable or represent an HLA by its alphanumeric name, and have limited ability to generalize to the HLAs that are not seen in the training process. To address this challenge, we propose a neural network-based method named Deep learning Prediction of TCR-HLA association (DePTH) to predict TCR-HLA associations based on their amino acid sequences. We demonstrate that DePTH is capable of making reasonable predictions for TCR-HLA associations, even when neither the HLA nor the TCR have been included in the training dataset. Furthermore, we establish that DePTH can be used to quantify the functional similarities among HLA alleles, and that these HLA similarities are associated with the survival outcomes of cancer patients who received immune checkpoint blockade treatments.