Biology subjects

Oyon-Olea, L.

Publications and source records attributed to Oyon-Olea, L..

3 recordsLinked to original sources

bioRxiv2026

Structure-function profiling identifies determinants of TCR-T cell therapeutic efficacy

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.

immunology↗

bioRxiv2026

Structural presentation of amyloid β by HLA

HLA-DR-restricted T-cell reactivity to amyloid {beta} (A{beta}) has been associated with Alzheimers disease (AD), but structural evidence for HLA presentation of A{beta}-derived peptides remains elusive. We present the crystal structure of the A{beta}1-15 fragment bound to HLA-DR1, providing, to the best of our knowledge, the first experimental structure of an Alzheimers A{beta} peptide bound to an HLA molecule. The molecular architecture of this complex defines a peptide:MHC interaction dictated by engagement of A{beta}1-15 peptide central core with further involvement of N- and C-terminal peptide flanks. The structure reveals that DR{beta}1 Arg70, a polymorphic position, directly binds P4 and P5 through polar contacts, providing a rationale for HLA-DRB allelic bias underpinning accommodation of A{beta}1-15. We also describe the A{beta}1-15:HLA-DRB1 surface topology, informing a candidate binding surface for potential T-cell recognition. Collectively, these findings contribute a structural framework for further research in the context of A{beta}-specific CD4+ T-cell autoreactivity in AD.

neuroscience↗

bioRxiv2025

Robust TCR production for the structural study of TCR-pMHC complexes

A precise comprehension of how T cell receptors (TCRs) engage their antigens is pivotal for advancing basic research and T cell immunotherapy in cancer. While TCR refolding from inclusion bodies has greatly facilitated X-ray studies over the past decades, the procedures remain labor-intensive and can yield poorly. We have developed a simplified strategy for efficient production of soluble TCRs in CHO cells which, coupled with the removal of N-glycosylation, enable structural studies of TCR-pMHC complexes. An equivalent of just 20 ml of cell culture delivered sufficient deglycosylated TCR (dgTCR) to screen, upon complexation with a cognate pMHC, over 350 crystallization conditions and obtain a high-resolution dataset. This approach illustrates an effective alternative for TCR production to support studies devoted to research and development of TCRs.

immunology↗