Structural characterization and AlphaFold modeling of human T cell receptor recognition of NRAS cancer neoantigens
Daichao Wu1,2, Rui Yin2,3, Guodong Chen1
1Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Laboratory of Structural Immunology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
Abstract:
T cell receptors (TCRs) that recognize cancer neoantigens are important for anti-cancer immune responses and immunotherapy. Understanding the structural basis of TCR recognition of neoantigens provides insights into their exquisite specificity and can enable design of optimized TCRs. We determined crystal structures of a human TCR in complex with NRAS Q61K and Q61R neoantigen peptides and HLA-A1 MHC, revealing the molecular underpinnings for dual recognition and specificity versus wild-type NRAS peptide. We then used multiple versions of AlphaFold to model the corresponding complex structures, given the challenge of immune recognition for such methods. Interestingly, one implementation of AlphaFold2 (TCRmodel2) was able to generate accurate models of the complexes, while AlphaFold3 also showed strong performance, although success was lower for other complexes. This study provides insights into TCR recognition of a shared cancer neoantigen, as well as the utility and practical considerations for using AlphaFold to model TCR-peptide-MHC complexes.
Insights
T cell receptors (TCRs) recognizing cancer neoantigens are key to immunotherapy. This study reveals TCR structural insights for dual neoantigen recognition and evaluates AlphaFold
Area of Science:
- Structural biology and immunology
- Cancer immunotherapy research
Background:
- T cell receptors (TCRs) are crucial for recognizing cancer neoantigens, driving anti-cancer immunity and immunotherapy efficacy.
- Understanding TCR-neoantigen-MHC interactions is vital for elucidating specificity and designing improved TCRs.
Purpose of the Study:
- To determine the structural basis of a human TCR's dual recognition of NRAS Q61K and Q61R neoantigen peptides.
- To assess the utility of AlphaFold models for predicting TCR-peptide-MHC complex structures.
Main Methods:
- X-ray crystallography was used to determine the structures of a human TCR complexed with NRAS Q61K/Q61R neoantigen peptides and HLA-A1 MHC.
- Multiple AlphaFold versions (including AlphaFold2 and AlphaFold3) were employed to model these TCR-peptide-MHC complexes.
Main Results:
- Crystal structures revealed the molecular details underlying the TCR's dual recognition and specificity for the Q61K and Q61R neoantigens compared to the wild-type.
- AlphaFold2 (TCRmodel2) successfully generated accurate models of the TCR-peptide-MHC complexes.
- AlphaFold3 demonstrated strong performance, though accuracy varied across different modeled complexes.
Conclusions:
- This research provides critical insights into the structural mechanisms of TCR recognition for a shared cancer neoantigen.
- The study highlights the potential and practical considerations of using AlphaFold for modeling TCR-peptide-MHC interactions in cancer research.
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