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Structural basis for self-discrimination by neoantigen-specific TCRs

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  • John P. Finnigan

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Mount Sinai Hospital
    Brigham and Women’s Hospital)

  • Jenna H. Newman

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Mount Sinai Hospital)

  • Yury Patskovsky

    (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)

  • Andrew S. Ishizuka

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health
    Barinthus Biotherapeutics)

  • Geoffrey M. Lynn

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health
    Barinthus Biotherapeutics)

  • Robert A. Seder

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Michelle Krogsgaard

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

  • Nina Bhardwaj

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Mount Sinai Hospital
    Parker Institute for Cancer Immunotherapy)

Abstract

T cell receptors (TCR) are pivotal in mediating tumour cell cytolysis via recognition of mutation-derived tumour neoantigens (neoAgs) presented by major histocompatibility class-I (MHC-I). Understanding the factors governing the emergence of neoAg from somatic mutations is a major focus of current research. However, the structural and cellular determinants controlling TCR recognition of neoAgs remain poorly understood. This study describes the multi-level analysis of a model neoAg from the B16F10 murine melanoma, H2-Db/Hsf2 p.K72N68-76, as well as its cognate TCR 47BE7. Through cellular, molecular and structural studies we demonstrate that the p.K72N mutation enhances H2-Db binding, thereby improving cell surface presentation and stabilizing the TCR 47BE7 epitope. Furthermore, TCR 47BE7 exhibited high functional avidity and selectivity, attributable to a broad, stringent, binding interface enabling recognition of native B16F10 despite low antigen density. Our findings provide insight into the generation of anchor-residue modified neoAg, and emphasize the value of molecular and structural investigations of neoAg in diverse MHC-I contexts for advancing the understanding of neoAg immunogenicity.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46367-9
    DOI: 10.1038/s41467-024-46367-9
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