Structure-Based, Rational Design of T Cell Receptors

Area of Science:

• Immunology and Cancer Therapy
• Computational Biology and Protein Engineering

Background:

• Adoptive cell transfer with engineered T cells shows promise for metastatic melanoma.
• T cell receptor (TCR) modifications can enhance antigen binding and T cell activation.
• Understanding TCR-pMHC interactions is crucial for optimizing engineered T cells.

Purpose of the Study:

• To develop a structure-based computational approach for rationally designing enhanced TCR sequences.
• To improve the binding affinity and functional activity of TCRs targeting cancer antigens.
• To create a pipeline for engineering TCRs for adoptive cell therapies in melanoma.

Main Methods:

• Utilized MM-GBSA free energy decomposition to analyze TCR/peptide-MHC (pMHC) interactions.
• Developed a novel structure-based protein engineering method to design new TCR sequences.
• Employed homology modeling (TCRep 3D) and molecular dynamics to model TCR-pMHC complexes and interactions.

Main Results:

• Designed TCR sequences showed up to 150-fold increase in pMHC binding affinity while maintaining specificity.
• Engineered CD8+ T cells expressing modified TCRs exhibited enhanced functional activity.
• Optimal T cell activity was observed within a specific affinity range (KD ≈ 1–5 μM), with higher affinities leading to reduced function.

Conclusions:

• The developed computational approach enables rational design of TCRs with improved therapeutic potential.
• This strategy successfully enhanced T cell function for adoptive cell therapy applications.
• The methods are applicable to TCRs lacking experimental structural data, broadening their utility.