Structure-function profiling identifies determinants of TCR-T cell therapeutic efficacy
- 1Navarrabiomed
Abstract
Glypican-3 (GPC3) is a promising target in adoptive T-cell therapy for hepatocellular carcinoma (HCC). TCR-A and TCR-B are two recently identified GPC3-specific TCRs recognizing the same HLA-A*02:01-restricted epitope but displaying markedly different therapeutic efficacy. To define the determinants of productive TCR-antigen recognition, we integrated high-resolution structures of both binary pMHC and ternary TCR:pMHC complexes, biolayer interferometry, peptide mutagenesis, target-cell conjugation assays, repetitive antigen challenge (RAC) and in vivo models. Structurally, conformational permissiveness of the immunodominant GPC3(522-530) peptide within HLA-A*02:01's groove is central for productive TCR docking, with TCR-B presenting slower association but prolonged dwell time. Functional divergence emerged during target-cell engagement and amplified under RAC conditions, where TCR-B sustained cytotoxic activity while TCR-A progressively lost function. This superior functional endurance translated into complete tumor eradication and durable responses in vivo. These findings provide a mechanistic basis and a conceptual framework for the selection and optimization of TCRs for adoptive immunotherapy.
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BibTeX
@misc{oyonolea2026structurefunction,
title = {{Structure-function profiling identifies determinants of TCR-T cell therapeutic efficacy}},
author = {L. Oyon-Olea and E. Vercher and G. Dichiara-Rodriguez and E. Erausquin and S. Hervas-Stubbs and J. Lopez-Sagaseta},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.750028},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.750028v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Structure-function profiling identifies determinants of TCR-T cell therapeutic efficacy
AU - L. Oyon-Olea
AU - E. Vercher
AU - G. Dichiara-Rodriguez
AU - E. Erausquin
AU - S. Hervas-Stubbs
AU - J. Lopez-Sagaseta
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.750028
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.750028v1
AB - Glypican-3 (GPC3) is a promising target in adoptive T-cell therapy for hepatocellular carcinoma (HCC). TCR-A and TCR-B are two recently identified GPC3-specific TCRs recognizing the same HLA-A*02:01-restricted epitope but displaying markedly different therapeutic efficacy. To define the determinants of productive TCR-antigen recognition, we integrated high-resolution structures of both binary pMHC and ternary TCR:pMHC complexes, biolayer interferometry, peptide mutagenesis, target-cell conjugation assays, repetitive antigen challenge (RAC) and in vivo models. Structurally, conformational permissiveness of the immunodominant GPC3(522-530) peptide within HLA-A*02:01's groove is central for productive TCR docking, with TCR-B presenting slower association but prolonged dwell time. Functional divergence emerged during target-cell engagement and amplified under RAC conditions, where TCR-B sustained cytotoxic activity while TCR-A progressively lost function. This superior functional endurance translated into complete tumor eradication and durable responses in vivo. These findings provide a mechanistic basis and a conceptual framework for the selection and optimization of TCRs for adoptive immunotherapy.
ER -