Structural basis for self-discrimination by neoantigen-specific TCRs

John P. Finnigan, Jenna H. Newman, Yury Patskovsky, Larysa Patskovska, Andrew S. Ishizuka, Geoffrey M. Lynn, Robert A. Seder, Michelle Krogsgaard () and Nina Bhardwaj ()
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John P. Finnigan: Icahn School of Medicine at Mount Sinai
Jenna H. Newman: Icahn School of Medicine at Mount Sinai
Yury Patskovsky: New York University Grossman School of Medicine
Larysa Patskovska: New York University Grossman School of Medicine
Andrew S. Ishizuka: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Geoffrey M. Lynn: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Robert A. Seder: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Michelle Krogsgaard: New York University Grossman School of Medicine
Nina Bhardwaj: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46367-9

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