Profiling antigen-binding affinity of B cell repertoires in tumors by deep learning predicts immune-checkpoint inhibitor treatment outcomes.

Journal: Nature cancer
Published Date: Jun 27, 2025

Abstract

The capability to profile the landscape of antigen-binding affinities of a vast number of antibodies (B cell receptors, BCRs) will provide a powerful tool to reveal biological insights. However, experimental approaches for detecting antibody-antigen interactions are costly and time-consuming and can only achieve low-to-mid throughput. In this work, we developed Cmai (contrastive modeling for antigen-antibody interactions) to address the prediction of binding between antibodies and antigens that can be scaled to high-throughput sequencing data. We devised a biomarker based on the output from Cmai to map the antigen-binding affinities of BCR repertoires. We found that the abundance of tumor antigen-targeting antibodies is predictive of immune-checkpoint inhibitor (ICI) treatment response. We also found that, during immune-related adverse events (irAEs) caused by ICI, humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. We used Cmai to construct a BCR-based irAE risk score, which predicted the timing of the occurrence of irAEs.

Authors

  • Bing Song
    ImmunityBio, 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
  • Kaiwen Wang
    Department of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
  • Saiyang Na
    Department of Computer Science and Engineering, University of Texas at Arlington, Arlington, TX, USA.
  • Jia Yao
    Experimental Center, Xi'an Hospital of Traditional Chinese Medicine, No.69 Feng Cheng 8th Road, Weiyang District, Xi'an, 710021, China.
  • Farjana J Fattah
    Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Alexandra L Martin
    AdventHealth Medical Group, Wesley Chapel, FL, USA.
  • Mitchell S von Itzstein
    Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • Donghan M Yang
    Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
  • Jialiang Liu
    Quantitative Biomedical Research Center, Department of Health Data Sciences and Biostatistics, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Yaming Xue
    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Chaoying Liang
    Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Yuzhi Guo
    Department of Computer Science and Engineering, University of Texas at Arlington, Arlington, Texas, USA.
  • Indu Raman
    Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Chengsong Zhu
    Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Jonathan E Dowell
    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Jade Homsi
    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Sawsan Rashdan
    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Shengjie Yang
    Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Mary E Gwin
    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Tuoqi Wu
    Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • David Hsiehchen
    Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Yvonne Gloria-McCutchen
    Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Catherine Pei-Ju Lu
    The Hansjörg Wyss Department of Plastic Surgery and Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA.
  • Prithvi Raj
    Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Xiao-Chen Bai
    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Jun Wang
    Department of Speech, Language, and Hearing Sciences and the Department of Neurology, The University of Texas at Austin, Austin, TX 78712, USA.
  • Jose Conejo-Garcia
    Department of Integrative Immunobiology, Duke School of Medicine, Durham, NC, USA.
  • Yang Xie
    Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5325 Harry Hines Blvd, Dallas, TX, 75390, USA.
  • Junzhou Huang
  • David E Gerber
    Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • Tao Wang
    Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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