Structural basis for oligoclonal T cell recognition of a shared NRAS cancer neoantigen

T cell receptors (TCRs) specific for cancer neoantigens are important for anti-tumor immunity and immunotherapy. To understand the structural basis for T cell recognition of cancer neoantigens, we studied oligoclonal TCRs from patients with melanoma that recognize a neoepitope arising from a driver mutation in NRAS (NRAS Q61K ) presented by HLA-A1. Structures of these TCRs in unbound form and bound to NRAS Q61K -HLA-A1 revealed that they employ chemically distinct strategies and engagement modes to distinguish between mutant and wild-type NRAS. The structures explain how the NRAS Q61K mutation rendered a self-antigen visible to T cells. We additionally benchmarked AlphaFold-based modeling of these complexes, showing that predictive accuracy varies markedly across TCR-peptide-MHC targets. We found that conformational plasticity can dramatically impact complex assembly accuracy. These findings define the basis for TCR recognition of a cancer neoantigen and provide stringent tests for computational modeling of TCR-peptide-MHC interactions relevant to cancer immunotherapy.