Rapid assessment of T-cell receptor specificity of the immune repertoire

Accurate assessment of T-cell-receptor (TCR)–antigen specificity across the whole immune repertoire 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–peptide systems. Here, we introduce RACER, a pairwise energy model capable of rapid assessment of TCR–peptide affinity for entire immune repertoires. 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 TCR–peptide system. When applied to simulate thymic selection of a major-histocompatibility-complex (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 computational challenge of reliably identifying properties of tumor antigen-specific T-cells at the level of an individual patient’s immune repertoire.