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<p>The immune checkpoint inhibitors have demonstrated promising clinical efficacy across various tumour types, yet the percentage of patients who benefit from them remains low. The bindings between tumour antigens and human leukocyte antigen class I/T cell receptor molecules determine the antigen presentation and T cell activation, thereby playing an important role in the immunotherapy response. In this paper, we propose UnifyImmun, a unified cross-attention transformer model designed to simultaneously predict the bindings of peptides to both receptors, providing more comprehensive evaluation of antigen immunogenicity. We devise a two-phase strategy using virtual adversarial training that enables these two tasks to reinforce each other mutually, by compelling the encoders to extract more expressive features. Our method demonstrates superior performance in predicting both peptide-HLA and peptide-TCR binding on multiple independent and external test sets. Notably, on a large-scale COVID-19 peptide-TCR binding test set without any seen peptide in the training set, our method outperforms the current state-of-the-art methods by more than 10%. The predicted binding scores significantly correlate with the immunotherapy response and clinical outcomes on two clinical cohorts. Furthermore, the cross-attention scores and integrated gradients reveal the amino acid sites critical for peptide binding to receptors. In essence, our approach marks an essential step towards comprehensive evaluation of antigen immunogenicity.</p>

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A unified cross-attention model for predicting antigen binding specificity to both HLA and TCR molecules

  • 期刊论文

  • 发表日期：

    2025年1月28日

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  • Chenpeng Yu,
  • Xing Fang,
  • Shiye Tian,
  • Hui Liu

摘要

The immune checkpoint inhibitors have demonstrated promising clinical efficacy across various tumour types, yet the percentage of patients who benefit from them remains low. The bindings between tumour antigens and human leukocyte antigen class I/T cell receptor molecules determine the antigen presentation and T cell activation, thereby playing an important role in the immunotherapy response. In this paper, we propose UnifyImmun, a unified cross-attention transformer model designed to simultaneously predict the bindings of peptides to both receptors, providing more comprehensive evaluation of antigen immunogenicity. We devise a two-phase strategy using virtual adversarial training that enables these two tasks to reinforce each other mutually, by compelling the encoders to extract more expressive features. Our method demonstrates superior performance in predicting both peptide-HLA and peptide-TCR binding on multiple independent and external test sets. Notably, on a large-scale COVID-19 peptide-TCR binding test set without any seen peptide in the training set, our method outperforms the current state-of-the-art methods by more than 10%. The predicted binding scores significantly correlate with the immunotherapy response and clinical outcomes on two clinical cohorts. Furthermore, the cross-attention scores and integrated gradients reveal the amino acid sites critical for peptide binding to receptors. In essence, our approach marks an essential step towards comprehensive evaluation of antigen immunogenicity.