Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-12441-w
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Funding
- Bloodwise [13004]
- Cell Medica
- Medical Research Council
- CRUK Experimental Cancer Medicine Centre
- NIHR UCL/UCLH Biomedical Research Centre
- Wellcome Trust
- Wellcome Trust Investigator Award [100326/Z/12/Z, 099266/Z/12/Z]
- PPP Allowance by Health Holland, Top Sector Life Sciences and Health
- Wellcome Trust [099266/Z/12/Z] Funding Source: Wellcome Trust
- MRC [G0701703] Funding Source: UKRI
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TCR-gene-transfer is an efficient strategy to produce therapeutic T cells of defined antigen specificity. However, there are substantial variations in the cell surface expression levels of human TCRs, which can impair the function of engineered T cells. Here we demonstrate that substitutions of 3 amino acid residues in the framework of the TCR variable domains consistently increase the expression of human TCRs on the surface of engineered T cells. The modified TCRs mediate enhanced T cell proliferation, cytokine production and cytotoxicity, while reducing the peptide concentration required for triggering effector function up to 3000-fold. Adoptive transfer experiments in mice show that modified TCRs control tumor growth more efficiently than wild-type TCRs. Our data indicate that simple variable domain modifications at a distance from the antigen-binding loops lead to increased TCR expression and improved effector function. This finding provides a generic platform to optimize the efficacy of TCR gene therapy in humans.
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