Predicting TCR-pMHC Binding by Reinforcement Learning

Abstract The binding between T cell receptors (TCRs) and peptide-major histocompat-ibility complexes (pMHCs) is fundamental to the immune system’s ability to recognize and eliminate pathogens. Accurate prediction of TCR-pMHC inter-actions holds significant promise for advancing cancer immunotherapy, vaccine design, and autoimmune disease research. However, existing approaches often treat the sequences, structures, and functions of TCRs, peptides, and MHC molecules in isolation, neglecting their interdependencies and hence limiting the prediction accuracy. In this study, we present ProTCR, a novel approach that integrates sequence, structural, and functional information within a reinforce-ment learning framework, offering a new paradigm for predicting TCR-pMHC binding. The reinforcement learning optimization enables ProTCR to generate TCR-pMHC sequences with enhanced binding propensity, thereby improving prediction accuracy. On benchmark datasets such as IEDB and VDJdb, ProTCR achieves an AUROC of 0.75, outperforming state-of-the-art methods by 32.7%, while offering interpretable insights into the structural and sequence determi-nants of binding. We further validate ProTCR using TCRs and neoantigens derived from a cervical cancer patient via proteogenomic profiling. Our analysis reveals a strong correlation between T cell clonal expansion and ProTCR-predicted TCR-peptide binding scores, supporting the biological relevance of the model. Additionally, ProTCR demonstrates robust performance in predict-ing SARS-CoV-2 TCR-pMHC complexes and generating MHC-specific peptides with potential applications in peptide-based immunotherapies. Collectively, these findings establish ProTCR as a powerful and interpretable tool for TCR-pMHC binding prediction, with broad utility across immunology research and translational applications.