| First Author | Finnigan JP | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 2140 |
| PubMed ID | 38459027 | Mgi Jnum | J:352004 |
| Mgi Id | MGI:7613398 | Doi | 10.1038/s41467-024-46367-9 |
| Citation | Finnigan JP, et al. (2024) Structural basis for self-discrimination by neoantigen-specific TCRs. Nat Commun 15(1):2140 |
| abstractText | 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-D(b)/Hsf2 p.K72N(68-76), as well as its cognate TCR 47BE7. Through cellular, molecular and structural studies we demonstrate that the p.K72N mutation enhances H2-D(b) 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. |
