Structural basis for TCR recognition of a Rac1 neoantigen arising from anchor residue mutation.

Area of Science:

• Immunology
• Structural Biology
• Oncology

Background:

• T cell receptor (TCR)-based immunotherapy targets cancer neoantigens.
• Neoantigens typically arise from mutations in exposed residues for TCR recognition.

Purpose of the Study:

• To describe a novel melanoma neoantigen, Rac1^P29S, and its interaction with a tumor-specific TCR.
• To elucidate the structural basis of TCR recognition for this unique neoantigen.

Main Methods:

• Determined the structures of the Rac1^P29S-HLA-A2 complex.
• Determined the structure of the Rac1^P29S-HLA-A2 complex bound to tumor-specific TCR 5934.

Main Results:

• The Rac1^P29S mutation at an anchor residue allows MHC presentation of the mutant peptide.
• TCR 5934 recognizes the Rac1^P29S peptide by engaging a non-mutated C-terminal residue, distinct from typical TCR binding.
• Structural analysis revealed how the P29S mutation renders the Rac1 self-peptide detectable by T cells.

Conclusions:

• The Rac1^P29S neoantigen's immunogenicity is driven by an anchor mutation, enabling MHC presentation.
• TCR 5934's recognition mechanism provides a novel paradigm, differing from TCRs that target mutated residues.
• These structural insights can guide the design of advanced TCR-based cancer immunotherapies.