Abstract Accurate assessment of TCR-antigen specificity at the whole immune repertoire level lies at the heart of improved cancer immunotherapy, but predictive models capable of high-throughput assessment of TCR-peptide pairs are lacking. Recent advances in deep sequencing and crystallography have enriched the data available for studying TCR-p-MHC systems. Here, we introduce a pairwise energy model, RACER, for rapid assessment of TCR-peptide affinity at the immune repertoire level. RACER applies supervised machine learning to efficiently and accurately resolve strong TCR-peptide binding pairs from weak ones. The trained parameters further enable a physical interpretation of interacting patterns encoded in each specific TCR-p-MHC system. When applied to simulate thymic selection of an MHC-restricted T-cell repertoire, RACER accurately estimates recognition rates for tumor-associated neoantigens and foreign peptides, thus demonstrating its utility in helping address the large computational challenge of reliably identifying the properties of tumor antigen-specific T-cells at the level of an individual patient’s immune repertoire.

Rapid Assessment of T-Cell Receptor Specificity of the Immune Repertoire