Computational design of optimized and preferentially paired human TCR constant regions for improved T cell function.

Authors

Maria Radman, Astar Shamul-Raybi, Jake Parker, Sarel J Fleishman, Cyrille J Cohen

Published in

Science advances. Volume 12. Issue 39. Pages eaeb9189. Sep 25, 2026. Epub Sep 23, 2026.

Abstract

T cell receptor (TCR) gene transfer is a promising approach for cancer immunotherapy, but its efficacy is limited by mispairing of TCR chains, which reduces surface expression and may generate off-target specificities. We applied the PROSS and FuncLib algorithms to engineer human TCR constant regions for improved stability and preferential pairing. After several screening rounds, we identified a variant, termed structurally enhanced TCR (SET), that exhibited markedly enhanced surface expression, functional avidity, and reduced mispairing. SET-expressing T cells secreted higher cytokine levels, displayed increased activation, and mediated superior cytotoxicity. Notably, SET demonstrated function in CD4⁺ T cells and mediated potent tumor control in xenograft models, significantly delaying tumor growth and improving survival. SET's benefits were reproducible across six different TCRs, supporting its broad applicability. These findings highlight the potential of rational design to improve the potency of TCR-based therapies.

PMID:
42777048
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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