MM-GBSA binding free energy decomposition and T cell receptor engineering

Area of Science:

• Immunology
• Computational Biology
• Oncology

Background:

• T-cell receptor (TCR) recognition of peptide-MHC complexes is crucial for anti-viral and anti-tumor immunity.
• TCR affinity for peptide-MHC complexes significantly influences T-cell activation.
• Previous studies validated binding free energy decomposition (BFED) for analyzing TCR-peptide-MHC interactions.

Purpose of the Study:

• To develop a rational approach for designing sequence modifications in TCRs to enhance affinity for specific tumor epitopes.
• To engineer TCRs targeting the NY-ESO-1 antigen presented by HLA-A2 for potential cancer immunotherapy.
• To evaluate the in vitro functionality of modified TCRs in T-cells.

Main Methods:

• Utilized a binding free energy decomposition (BFED) approach, building upon MM-GBSA methods.
• Designed sequence modifications for a TCR targeting the HLA-A2 restricted NY-ESO-1 tumor epitope.
• Tested engineered TCRs in vitro, assessing T-cell functionality, killing capacity, and proliferation.

Main Results:

• The BFED approach provides a reliable description of TCR-peptide-MHC interaction energetics.
• Engineered TCRs with modified sequences demonstrated increased affinity for the target epitope.
• T-cells expressing modified TCRs exhibited enhanced anti-tumor activity, including improved target cell killing and proliferation.

Conclusions:

• Rational TCR design based on computational energetics is feasible for enhancing T-cell responses.
• Modified TCRs targeting tumor antigens like NY-ESO-1 show promise for adoptive cell therapy.
• This approach offers a pathway for developing more effective cancer immunotherapies.