Structural Basis for Self-Discrimination by Neoantigen-Specific TCRs

Physical interactions between T cell receptors (TCRs) and mutation-derived tumour neoantigens (neoAg) presented by major histocompatibility class-I (MHC-I) enable sensitive and specific cytolysis of tumour cells. Adoptive transfer of neoAg-reactive T cells in patients is correlated with response to immunotherapy; however, the structural and cellular mechanisms of neoAg recognition remain poorly understood. We have identified multiple cognate neoAg:TCRs from B16F10, a common murine implantable tumour model of melanoma. We identified a high affinity TCR targeting H2-D(b)-restricted Hsf2(K72N) that conferred specific recognition of B16F10 in vitro and in vivo. Structural characterization of the peptide-MHC (pMHC) binary and pMHC:TCR ternary complexes yielded high-resolution crystal structures, revealing the formation of a solvent-exposed hydrophobic arch in H2-D(b) that enables multiple intermolecular contacts between pMHC and the TCR. These features of structural stability strikingly mimic that of a previously published influenza peptide-H2-D(b) complex and its corresponding TCR, suggesting that there are shared structural motifs between neoantigens and viral peptides that explain their shared immunogenicity.