Structural basis for T-cell receptor recognition of p53^Y220D, a human cancer neoantigen

Area of Science:

• Immunology
• Structural Biology
• Oncology

Background:

• Adoptive cell therapy (ACT) utilizes tumor-specific T cells for cancer regression.
• T cells recognize cancer neoantigens, which arise from mutations in self-antigens.
• Understanding T-cell recognition of neoantigens is key for advancing cancer therapies.

Purpose of the Study:

• To determine the atomic-level structure of a T-cell receptor (TCR 4414A) recognizing a p53 neoepitope.
• To investigate how a specific mutation (p53^Y220D) alters peptide presentation and T-cell detection.
• To provide insights into the molecular basis of TCR specificity for cancer neoantigens.

Main Methods:

• X-ray crystallography was used to determine the structures of TCR 4414A bound to HLA-A2/p53^Y220D.
• Structures of unbound wild-type and mutant p53-HLA-A2 ligands were also solved.
• Structural analysis focused on TCR-peptide-MHC interactions and the impact of the Y220D mutation.

Main Results:

• The Y220D mutation induces a conformational change in the p53 neoepitope, making it detectable by TCR 4414A.
• TCR 4414A specifically interacts with the mutated residue (Y220D) at the center of the peptide.
• The TCR avoids interactions with conserved peptide regions, ensuring high specificity for the mutant p53 over wild-type.

Conclusions:

• TCR 4414A achieves highly specific recognition of the p53^Y220D neoantigen over wild-type p53.
• This specificity is critical for minimizing off-target toxicities in ACT.
• The findings provide a structural basis for designing TCRs with enhanced specificity for cancer neoantigens.