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Molecular mechanism of phosphopeptide neoantigen immunogenicity

Author

Listed:
  • Yury Patskovsky

    (New York University Grossman School of Medicine
    Laura and Isaac Perlmutter Cancer Center at NYU Langone Health)

  • Aswin Natarajan

    (New York University Grossman School of Medicine
    Laura and Isaac Perlmutter Cancer Center at NYU Langone Health)

  • Larysa Patskovska

    (New York University Grossman School of Medicine
    Laura and Isaac Perlmutter Cancer Center at NYU Langone Health)

  • Samantha Nyovanie

    (New York University Grossman School of Medicine
    Laura and Isaac Perlmutter Cancer Center at NYU Langone Health)

  • Bishnu Joshi

    (Agenus)

  • Benjamin Morin

    (Agenus)

  • Christine Brittsan

    (Agenus)

  • Olivia Huber

    (Agenus)

  • Samuel Gordon

    (Agenus)

  • Xavier Michelet

    (Agenus)

  • Florian Schmitzberger

    (Agenus)

  • Robert B. Stein

    (Agenus)

  • Mark A. Findeis

    (Agenus)

  • Andy Hurwitz

    (Agenus)

  • Marc Dijk

    (Agenus)

  • Eleni Chantzoura

    (Agenus)

  • Alvaro S. Yague

    (Agenus)

  • Daniel Pollack Smith

    (Agenus)

  • Jennifer S. Buell

    (Agenus)

  • Dennis Underwood

    (Agenus)

  • Michelle Krogsgaard

    (New York University Grossman School of Medicine
    Laura and Isaac Perlmutter Cancer Center at NYU Langone Health)

Abstract

Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747–755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization.

Suggested Citation

  • Yury Patskovsky & Aswin Natarajan & Larysa Patskovska & Samantha Nyovanie & Bishnu Joshi & Benjamin Morin & Christine Brittsan & Olivia Huber & Samuel Gordon & Xavier Michelet & Florian Schmitzberger , 2023. "Molecular mechanism of phosphopeptide neoantigen immunogenicity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39425-1
    DOI: 10.1038/s41467-023-39425-1
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    References listed on IDEAS

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    1. Yu-Ting Yen & May Chien & Pei-Yi Wu & Chi-Chang Ho & Chun-Te Ho & Kevin Chih-Yang Huang & Shu-Fen Chiang & K. S. Clifford Chao & William Tzu-Liang Chen & Shih-Chieh Hung, 2021. "Protein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Michal Bassani-Sternberg & Eva Bräunlein & Richard Klar & Thomas Engleitner & Pavel Sinitcyn & Stefan Audehm & Melanie Straub & Julia Weber & Julia Slotta-Huspenina & Katja Specht & Marc E. Martignoni, 2016. "Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry," Nature Communications, Nature, vol. 7(1), pages 1-16, December.
    3. Jeffrey M. Perkel, 2020. "The software that powers scientific illustration," Nature, Nature, vol. 582(7810), pages 137-138, June.
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    Cited by:

    1. John P. Finnigan & Jenna H. Newman & Yury Patskovsky & Larysa Patskovska & Andrew S. Ishizuka & Geoffrey M. Lynn & Robert A. Seder & Michelle Krogsgaard & Nina Bhardwaj, 2024. "Structural basis for self-discrimination by neoantigen-specific TCRs," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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