Patient-derived high functional avidity TCR empowers diverse T cell subsets for tumour immunotherapy
5 affiliations
- 1CAMS Oxford Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, University of Oxford
- 2MRC Translational Immune Discovery Unit (TIDU), MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine (RDM), University of Oxford
- 3Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust
- 4Oxford National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust
- 5Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Department of Medicine, University of Oxford
Abstract
Cancer-testis antigens (CTAs) are attractive targets for tumour immunotherapy due to their restricted expression in human malignancies and broad population-level prevalence. However, naturally occurring CTA-reactive T cells are often exhausted or functionally compromised, limiting their direct therapeutic utility. Here, using a non-viral orthotopic TCR replacement system, we systematically evaluated two patient-derived HLA-A*02:01-restricted TCRs specific for the synovial sarcoma X breakpoint 2 (SSX2) epitope SSX2 ₄₁₋₄₉ (KASEKIFYV). Although both TCRs conferred SSX2 specificity, one displayed markedly higher functional avidity and superior antigen responsiveness. Primary CD8 ⁺ T cells redirected with this high-avidity TCR showed CD8-independent recognition, enhanced tetramer binding, and stronger functional responses against SSX2-expressing tumour cells. Notably, the same TCR also redirected CD4 ⁺ T cells toward the MHC-I-restricted SSX2 epitope, inducing polyfunctional cytokine release and direct tumour cytotoxicity. Moreover, it remained highly functional when introduced into unconventional T cell subsets, including NKT and γδ T cells, thereby expanding the range of potential cellular platforms for TCR-based therapeutics. Together, these findings identify a naturally derived, high functional avidity SSX2-reactive TCR with broad activity across conventional and unconventional T cell subsets, supporting its further development for future TCR-T cell-based immunotherapies.
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BibTeX
@article{gao2026patientderived,
title = {{Patient-derived high functional avidity TCR empowers diverse T cell subsets for tumour immunotherapy}},
author = {Fei Gao and Yanchun Peng and Ji-Li Chen and Mariana Pereira Pinho and Xuan Yao and Yi-Ling Chen and Uzi Gileadi and Adam Bates and Craig Waugh and Paul Sopp and Nikolaos I. Kanellakis and Najib M. Rahman and Ricardo A. Fernandes and Graham S. Ogg and Tao Dong},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1964649},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1964649/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Patient-derived high functional avidity TCR empowers diverse T cell subsets for tumour immunotherapy
AU - Fei Gao
AU - Yanchun Peng
AU - Ji-Li Chen
AU - Mariana Pereira Pinho
AU - Xuan Yao
AU - Yi-Ling Chen
AU - Uzi Gileadi
AU - Adam Bates
AU - Craig Waugh
AU - Paul Sopp
AU - Nikolaos I. Kanellakis
AU - Najib M. Rahman
AU - Ricardo A. Fernandes
AU - Graham S. Ogg
AU - Tao Dong
PY - 2026
DA - 2026/10/19
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1964649
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1964649/full
AB - Cancer-testis antigens (CTAs) are attractive targets for tumour immunotherapy due to their restricted expression in human malignancies and broad population-level prevalence. However, naturally occurring CTA-reactive T cells are often exhausted or functionally compromised, limiting their direct therapeutic utility. Here, using a non-viral orthotopic TCR replacement system, we systematically evaluated two patient-derived HLA-A*02:01-restricted TCRs specific for the synovial sarcoma X breakpoint 2 (SSX2) epitope SSX2 ₄₁₋₄₉ (KASEKIFYV). Although both TCRs conferred SSX2 specificity, one displayed markedly higher functional avidity and superior antigen responsiveness. Primary CD8 ⁺ T cells redirected with this high-avidity TCR showed CD8-independent recognition, enhanced tetramer binding, and stronger functional responses against SSX2-expressing tumour cells. Notably, the same TCR also redirected CD4 ⁺ T cells toward the MHC-I-restricted SSX2 epitope, inducing polyfunctional cytokine release and direct tumour cytotoxicity. Moreover, it remained highly functional when introduced into unconventional T cell subsets, including NKT and γδ T cells, thereby expanding the range of potential cellular platforms for TCR-based therapeutics. Together, these findings identify a naturally derived, high functional avidity SSX2-reactive TCR with broad activity across conventional and unconventional T cell subsets, supporting its further development for future TCR-T cell-based immunotherapies.
SN - 1664-3224
ER -