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TCR-epiDiff:解决TCR生成和结合预测的双重挑战。

TCR-epiDiff: solving dual challenges of TCR generation and binding prediction.

作者信息

Seo Se Yeon, Rhee Je-Keun

机构信息

Department of Bioinformatics & Life Science, Soongsil University, Seoul 06978, Korea.

出版信息

Bioinformatics. 2025 Jul 1;41(Supplement_1):i125-i132. doi: 10.1093/bioinformatics/btaf202.


DOI:10.1093/bioinformatics/btaf202
PMID:40662810
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12261488/
Abstract

MOTIVATION: T cell receptors (TCRs) are fundamental components of the adaptive immune system, recognizing specific antigens for targeted immune responses. Understanding their sequence patterns is crucial for designing effective vaccines and immunotherapies. However, the vast diversity of TCR sequences and complex binding mechanisms pose significant challenges in generating TCRs that are specific to a particular epitope. RESULTS: Here, we propose TCR-epiDiff, a diffusion-based deep learning model for generating epitope-specific TCRs and predicting TCR-epitope binding. TCR-epiDiff integrates epitope information during TCR sequence embedding using ProtT5-XL and employs a denoising diffusion probabilistic model for sequence generation. Using external validation datasets, we demonstrate the ability to generate biologically plausible, epitope-specific TCRs. Furthermore, we leverage the model's encoder to develop a TCR-epitope binding predictor that shows robust performance on the external validation data. Our approach provides a comprehensive solution for both de novo generation of epitope-specific TCRs and TCR-epitope binding prediction. This capability provides valuable insights into immune diversity and has the potential to advance targeted immunotherapies. AVAILABILITY AND IMPLEMENTATION: The data and source codes for our experiments are available at: https://github.com/seoseyeon/TCR-epiDiff.

摘要

动机:T细胞受体(TCR)是适应性免疫系统的基本组成部分,可识别特定抗原以引发靶向免疫反应。了解其序列模式对于设计有效的疫苗和免疫疗法至关重要。然而,TCR序列的巨大多样性和复杂的结合机制给生成针对特定表位的TCR带来了重大挑战。 结果:在此,我们提出了TCR-epiDiff,一种基于扩散的深度学习模型,用于生成表位特异性TCR并预测TCR-表位结合。TCR-epiDiff在使用ProtT5-XL进行TCR序列嵌入期间整合表位信息,并采用去噪扩散概率模型进行序列生成。使用外部验证数据集,我们展示了生成生物学上合理的、表位特异性TCR的能力。此外,我们利用该模型的编码器开发了一种TCR-表位结合预测器,其在外部验证数据上表现出强大的性能。我们的方法为从头生成表位特异性TCR和TCR-表位结合预测提供了全面的解决方案。这种能力为免疫多样性提供了有价值的见解,并有可能推动靶向免疫疗法的发展。 可用性和实现方式:我们实验的数据和源代码可在以下网址获取:https://github.com/seoseyeon/TCR-epiDiff。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/9730ffb832eb/btaf202f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/f572b13fd014/btaf202f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/e8fa338ae796/btaf202f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/c84833336250/btaf202f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/d11bd66cd133/btaf202f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/9730ffb832eb/btaf202f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/f572b13fd014/btaf202f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/e8fa338ae796/btaf202f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/c84833336250/btaf202f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/d11bd66cd133/btaf202f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4db9/12261488/9730ffb832eb/btaf202f5.jpg

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[9]
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[10]
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本文引用的文献

[1]
Artificial intelligence-guided strategies for next-generation biological sequence design.

Natl Sci Rev. 2024-9-26

[2]
NeoTCR: an immunoinformatic database of experimentally-supported functional neoantigen-specific TCR sequences.

Genomics Proteomics Bioinformatics. 2024-2-3

[3]
A conditional protein diffusion model generates artificial programmable endonuclease sequences with enhanced activity.

Cell Discov. 2024-9-10

[4]
Cancer incidence and mortality in China, 2016.

J Natl Cancer Cent. 2022-2-27

[5]
Blind CT Image Quality Assessment Using DDPM-Derived Content and Transformer-Based Evaluator.

IEEE Trans Med Imaging. 2024-10

[6]
Designing meaningful continuous representations of T cell receptor sequences with deep generative models.

Nat Commun. 2024-5-20

[7]
Diffusion models in bioinformatics and computational biology.

Nat Rev Bioeng. 2024-2

[8]
The recent advancement of TCR-T cell therapies for cancer treatment.

Acta Biochim Biophys Sin (Shanghai). 2024-5-25

[9]
epiTCR: a highly sensitive predictor for TCR-peptide binding.

Bioinformatics. 2023-5-4

[10]
CAR-T: What Is Next?

Cancers (Basel). 2023-1-21

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