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Updated: May 25, 2025
Measuring TCR-pMHC Binding In Situ using a FRET-based Microscopy Assay
Published on: October 30, 2015
Tuning TCR complex recruitment to the T cell antigen coupler (TAC) enhances TAC-T cell function
Trevor M Morey1, Tania Benatar2, Stacey X Xu2
1Department of Biochemistry, University of Toronto, 661 University Avenue, MaRS Centre, West Tower, Room 1612, Toronto, ON, M5G 1M1, Canada.
Abstract:
The T cell antigen coupler (TAC) receptor is a novel synthetic receptor designed to maximize the therapeutic potential of T cells in the absence of tonic signaling or receptor-related toxicities. Prior studies indicated that TACs provide safe and long-lasting anti-tumor immunity in multiple preclinical models of solid tumors supported by mounting clinical evidence. TAC receptors function by targeting a cancer associated surface antigen while recapitulating natural T cell receptor (TCR) signaling, which involves both TCR/CD3 recruitment and intracellular CD4 co-receptor activity. While other receptor designs exist that redirect TCR signaling towards cancer associated antigens, the TAC technology is unique in that antigen binding is distinctly separated from TCR/CD3 complex recruitment. In the present study, we show that single amino-acid changes in the TAC domain responsible for TCR recruitment of a Claudin 18.2-directed TAC receptor led to enhanced in vivo functionality. Analyzing biophysical properties of the receptor suggests that TAC receptors with high TCR affinities are suboptimal compared to receptor constructs that show lower TCR affinities with notably fast off-rates. This work demonstrates that balancing TCR recruitment is critical when designing effective TAC T cell receptors, a concept that may apply more broadly to other therapeutic approaches relying on TCR signaling.
Insights
Optimizing T cell antigen coupler (TAC) receptors is key for effective cancer immunotherapy. Lower TCR affinities with fast off-rates enhance in vivo functionality, improving anti-tumor immunity.
Area of Science:
- Immunology
- Biotechnology
- Oncology
Background:
- T cell antigen coupler (TAC) receptors are synthetic receptors designed to enhance T cell-based cancer therapies.
- TACs aim to provide safe, long-lasting anti-tumor immunity by recapitulating natural T cell receptor (TCR) signaling.
- Unlike other designs, TAC technology separates antigen binding from TCR/CD3 complex recruitment.
Purpose of the Study:
- To investigate the impact of single amino-acid changes in the TAC domain on TCR recruitment.
- To analyze the biophysical properties and in vivo functionality of Claudin 18.2-directed TAC receptors.
- To determine the optimal balance of TCR affinity and off-rates for effective TAC T cell receptor design.
Main Methods:
- Engineered Claudin 18.2-directed TAC receptors with specific amino-acid alterations in the TCR recruitment domain.
- Evaluated in vivo functionality of modified TAC receptors in preclinical solid tumor models.
- Assessed biophysical properties, including TCR affinities and off-rates, of different TAC receptor constructs.
Main Results:
- Single amino-acid changes in the TAC domain significantly enhanced in vivo functionality.
- TAC receptors with high TCR affinities were suboptimal for anti-tumor activity.
- Receptor constructs with lower TCR affinities and fast off-rates demonstrated improved functionality.
Conclusions:
- Balancing TCR recruitment affinity and off-rates is critical for designing effective TAC T cell receptors.
- This optimization principle may extend to other therapeutic strategies involving TCR signaling.
- Fine-tuning TAC receptor design can enhance T cell-mediated anti-tumor immunity.
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