Molecular mechanisms of immunogenicity and TCR recognition of NRAS-derived public neoantigens 4770
Year: 2025
Type: article
Abstract: Description T cells use TCRs to recognize and mediate anti-cancer immune responses against “neoantigens” - cancer-specific mutant peptides displayed by MHC proteins. “Public neoantigens” are tumor antigens shared among individuals that can be ideal immunotherapy targets. The common NRAS Q61 mutations Q61R, Q61K, Q61L, and Q61H give rise to HLA-A*01:01 (A1) restricted public neoantigens. The current study aims to elucidate how these neoantigens are distinct from their wild type (WT) counterpart and the mechanisms of neoantigen specificity of a panel of patient-derived TCRs. Differential scanning fluorimetry shows that neoantigens bind with similar affinity as the WT to A1. The X-ray crystal structures of these neoantigen/WT-A1 complexes reveal that the sidechain of p7Q of the WT is bent and “tethered” to the α2 helix of A1 via H-bonds, resulting in a lower solvent accessible surface area than the p7 of neoantigens. The resulting structural differences between the neoantigens and WT could promote neoantigen-specific TCR interactions. Depicting an inverse affinity-specificity relationship, in surface plasmon resonance, the TCR with the highest specificity to a single neoantigen shows the lowest affinity. In crystal structures, a cross-reactive TCR predominantly contacts the penultimate p9E of neoantigens, bypassing the p7 mutation to facilitate cross-reactivity. We anticipate that understanding NRAS neoantigen antigenicity will aid in developing novel T cell-based cancer immunotherapies. Funding Sources NIH R01CA286507 Topic Categories Vaccines and Immunotherapy (VAC)
Source: The Journal of Immunology
Authors: Gihan Perera, Inaki Etxeberria, Christopher Klebanoff, Brian Baker
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416448999
FWCI:
Cites:
Cited by:
Related to: