A functionally validated TCR-pMHC database for TCR specificity model development

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Accurate prediction of TCR specificity forms a holy grail in immunology and large language models and computational structure predictions provide a path to achieve this. Importantly, current TCR-pMHC prediction models have been trained and evaluated using historical data of unknown quality. Here, we develop and utilize a high-throughput synthetic platform for TCR assembly and evaluation to assess a large fraction of VDJdb-deposited TCR-pMHC entries using a standardized readout of TCR function. Strikingly, this analysis demonstrates that claimed TCR reactivity is only confirmed for 50% of evaluated entries. Intriguingly, the use of TCRbridge to analyze AlphaFold3 confidence metrics reveals a substantial performance in distinguishing functionally validating and non-validating TCRs even though AlphaFold3 was not trained on this task, demonstrating the utility of the validated VDJdb (TCRvdb) database that we generated. We provide TCRvdb as a resource to the community to support training and evaluation of improved predictive TCR specificity models.

Authors 18

1. Marius Messemaker corresponding

   The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

2. Bjørn P. Y. Kwee

   The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

3. Živa Moravec

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

4. Daniel Álvarez Salmoral

   The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

5. Jos H. M. Urbanus

   The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

6. Sam de Paauw

   The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

7. Jeroen Geerligs

   The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

8. Rhianne Voogd

   The Netherlands Cancer Institute · Oncode Institute

   Affiliation as printed

   Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

   Oncode Institute, Utrecht, The Netherlands

9. Ben Morris

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

10. Aurélie Guislain

    The Netherlands Cancer Institute · Oncode Institute

    Affiliation as printed

    Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Oncode Institute, Utrecht, The Netherlands

11. Yael Winkler

    The Netherlands Cancer Institute · Oncode Institute

    Affiliation as printed

    Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Oncode Institute, Utrecht, The Netherlands

12. Matyas Iras

    The Netherlands Cancer Institute · Oncode Institute

    Affiliation as printed

    Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Oncode Institute, Utrecht, The Netherlands

13. Eric Marcus

    The Netherlands Cancer Institute

    Affiliation as printed

    AI for Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

14. Jonas Teuwen

    The Netherlands Cancer Institute

    Affiliation as printed

    AI for Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

15. Anastassis Perrakis

    The Netherlands Cancer Institute · Oncode Institute

    Affiliation as printed

    Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Oncode Institute, Utrecht, The Netherlands

16. Roderick L. Beijersbergen

    The Netherlands Cancer Institute

    Affiliation as printed

    Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

17. Wouter Scheper

    The Netherlands Cancer Institute

    Affiliation as printed

    Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

18. Ton N. Schumacher Aachen Department of Hematology, Leiden University Medical Center

    Leiden University Medical Center · The Netherlands Cancer Institute · Oncode Institute

    Affiliation as printed

    Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

    Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Oncode Institute, Utrecht, The Netherlands