THLANet: A deep learning framework for predicting TCR-pHLA binding in immunotherapy applications.

Adaptive immunity is a targeted immune response that enables the body to identify and eliminate foreign pathogens, playing a critical role in the anti-tumor immune response. Tumor cell expression of antigens forms the foundation for inducing this adaptive response. However, the human leukocyte antigens (HLA)-restricted recognition of antigens by T-cell receptors (TCR) limits their ability to detect all neoantigens, with only a small subset capable of activating T-cells. Accurately predicting neoantigen binding to TCR is, therefore, crucial for assessing their immunogenic potential in clinical settings. We present THLANet, a deep learning model designed to predict the binding specificity of TCR to neoantigens presented by class I HLAs. THLANet employs evolutionary scale modeling-2 (ESM-2), replacing the traditional embedding methods to enhance sequence feature representation. Using scTCR-seq data, we obtained the TCR immune repertoire and constructed a TCR-pHLA binding database to validate THLANet's clinical potential. The model's performance was further evaluated using clinical cancer data across various cancer types. Additionally, by analyzing divided complementarity-determining region (CDR3) sequences and simulating alanine scanning of antigen sequences, we provided new insights into the 3D binding interactions of TCRs and antigens. Predicting TCR-neoantigen pairing remains a significant challenge in immunology, THLANet provides accurate predictions using only the TCR sequence (CDR3β), antigen sequence, and class I HLA, offering novel insights into TCR-antigen interactions.