Structural insights and immunogenic enhancement of KRAS neoantigen recognition by TCRs in cancer immunotherapy 4724

Abstract Description For over 30 years, KRAS, a key oncogene, was deemed “undruggable” due to its intracellular nature and absence of a specific binding site, which poses a challenge for monoclonal antibodies and small molecule targeting. Immunotherapy offers a promising approach by leveraging T cell receptor (TCR) recognition of mutant KRAS peptides presented by human leukocyte antigen (HLA) class I on cancer cell surfaces. Driver mutations like KRAS-G12D generate public neoantigens, shared among patients, making them ideal targets for T-cell therapy. Our study aims to investigate the structural and biophysical basis for the specificity of five patient-derived TCRs that recognize the KRAS-G12D neoantigen presented by HLA-A11. Our data shows that all five TCRs recognize KRAS-G12D with high specificity. Structural analysis revealed a conserved conformational shift in the peptide upon TCR binding, with residues A5 and D6 orienting from an exposed to a downward-facing position, adopting a polyproline type II conformation upon TCR binding, indicating a potential shared recognition mechanism. Building on these insights, we aim to design a KRAS super-agonist by chemically modifying the KRAS-G12D peptide backbone to stabilize its TCR-bound conformation. These findings pave the way for transformative T cell -based immunotherapies targeting KRAS. Funding Sources Supported by NIH Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)