Phage display enables machine learning discovery of cancer antigen-specific TCRs

Sci Adv. 2025 Jun 13;11(24):eads5589. doi: 10.1126/sciadv.ads5589. Epub 2025 Jun 11.

Abstract

T cells targeting epitopes in infectious diseases or cancer play a central role in spontaneous and therapy-induced immune responses. Epitope recognition is mediated by the binding of the T cell receptor (TCR), and TCRs recognizing clinically relevant epitopes are promising for T cell-based therapies. Starting from a TCR targeting the cancer-testis antigen NY-ESO-1157-165 epitope, we built large phage display libraries of TCRs with randomized complementary determining region 3 of the β chain. The TCR libraries were panned against NY-ESO-1, which enabled us to collect thousands of epitope-specific TCR sequences. Leveraging these data, we trained a machine learning TCR-epitope interaction predictor and identified several epitope-specific TCRs from TCR repertoires. Cellular assays revealed that the predicted TCRs displayed activity toward NY-ESO-1 and no detectable cross-reactivity. Our work demonstrates how display technologies combined with TCR-epitope interaction predictors can effectively leverage large TCR repertoires for TCR discovery.

MeSH terms

  • Antigens, Neoplasm* / immunology
  • Cell Surface Display Techniques*
  • Epitopes, T-Lymphocyte / immunology
  • Humans
  • Machine Learning*
  • Membrane Proteins / immunology
  • Neoplasms* / immunology
  • Peptide Library*
  • Receptors, Antigen, T-Cell* / genetics
  • Receptors, Antigen, T-Cell* / immunology
  • Receptors, Antigen, T-Cell* / metabolism

Substances

  • Receptors, Antigen, T-Cell
  • Antigens, Neoplasm
  • Peptide Library
  • Epitopes, T-Lymphocyte
  • CTAG1B protein, human
  • Membrane Proteins