Structural characterization and AlphaFold modeling of human T cell receptor recognition of NRAS cancer neoantigens

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• T cell receptors (TCRs) are crucial for recognizing cancer neoantigens, driving anti-cancer immune responses and immunotherapy efficacy.
• Elucidating the structural basis of TCR-neoantigen recognition is vital for understanding specificity and designing improved TCR-based therapies.

Purpose of the Study:

• To determine the crystal structures of a human TCR complexed with NRAS Q61K and Q61R neoantigen peptides and HLA-A1.
• To investigate the molecular mechanisms underlying the TCR's dual recognition and specificity for neoantigenic versus wild-type NRAS peptides.
• To assess the utility and accuracy of AlphaFold AI models in predicting TCR-peptide-MHC complex structures.

Main Methods:

• X-ray crystallography was employed to determine the high-resolution structures of the TCR-neoantigen-MHC complexes.
• Multiple AlphaFold versions, including AlphaFold2 (TCRmodel2) and AlphaFold3, were utilized to model these complexes.
• Comparative analysis was performed between experimentally determined structures and AI-generated models.

Main Results:

• Crystal structures revealed the molecular details of a human TCR recognizing both NRAS Q61K and Q61R neoantigen peptides bound to HLA-A1.
• The structures elucidated the basis for the TCR's dual specificity compared to the wild-type NRAS peptide.
• AlphaFold2 (TCRmodel2) with enhanced sampling successfully modeled the TCR-peptide-MHC complexes, demonstrating strong performance.
• AlphaFold3 also showed promising results, though with variable success across different complexes.

Conclusions:

• This research provides critical structural insights into the recognition of a shared cancer neoantigen by a TCR.
• The study highlights the potential and practical considerations of employing AlphaFold for modeling TCR-peptide-MHC interactions.
• Findings can inform the rational design of TCR-based immunotherapies targeting specific cancer neoantigens.