Patient-derived high functional avidity TCR empowers diverse T cell subsets for tumour immunotherapy

Gao, F; Peng, Y; Chen, J-L; Pinho, MP; Yao, X; Chen, Y-L; Gileadi, U; Bates, A; Waugh, C; Sopp, P; Kanellakis, NI; Rahman, NM; Fernandes, RA; Ogg, GS; Dong, T; Pereira Pinho, M

Journal article

Patient-derived high functional avidity TCR empowers diverse T cell subsets for tumour immunotherapy

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 SSX241-49 (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.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Gao, F., Peng, Y., Chen, J.-L., Pinho, M., Yao, X., Chen, Y.-L., Gileadi, U., Bates, A., Waugh, C., Sopp, P., Kanellakis, N., Rahman, N., Fernandes, R., Ogg, G., Dong, T., & Pereira Pinho, M. (2026). Patient-derived high functional avidity TCR empowers diverse T cell subsets for tumour immunotherapy. Frontiers in Immunology, 17, 1964649–1964649.

MLA Style

Gao, F., et al. “Patient-Derived High Functional Avidity TCR Empowers Diverse T Cell Subsets for Tumour Immunotherapy.” Frontiers in Immunology, vol. 17, 2026, pp. 1964649–49.

Chicago Style

Gao, F., Y. Peng, J.-L. Chen, et al. 2026. “Patient-Derived High Functional Avidity TCR Empowers Diverse T Cell Subsets for Tumour Immunotherapy.” Frontiers in Immunology 17: 1964649–49.
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