Fiche publication
Date publication
février 2026
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ROSSI Cédric
Tous les auteurs :
Marcoux P, Gava F, Tosolini M, Gravelle P, Schniederjohann C, Quertinmont S, Serrat N, Bouquet F, Herter S, Tarte K, Roussel M, Sesques P, Bret C, Rossi C, Aubert P, Morschhauser F, Cartron G, Huber W, Dietrich S, Ysebaert L, Brousset P, Bruch PM, Pérez-Galán P, Bezombes C, Laurent C
Lien Pubmed
Résumé
Bispecific antibodies (bsAbs) such as glofitamab represent a promising therapeutic approach for relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL), but resistance mechanisms remain poorly understood. This study aimed to identify predictive markers of bsAbs resistance based on the response of 3D patient-derived lymphoma spheroids (PDLS) established from 39 R/R B-NHL samples. PDLS were treated with glofitamab for 3 days and B-cell depletion was quantified to assess the ex-vivo treatment response. Comprehensive immune profiling was performed on patient samples using multiparametric flow cytometry, single-cell RNA sequencing, CODEX spatial proteomics and functional assays. High responders to glofitamab possessed CD8+ T-cells with consistently higher cytotoxic and activation signatures across effector differentiation states, while low responders showed enrichment of exhausted CD8+ T-cell with enhanced expression of exhaustion markers (TIGIT, LAG3, PD1). Furthermore, low responders exhibited elevated functional CD4+ T-follicular helper (Tfh) cells in close proximity to malignant B-cell thus promoting their survival through IL21 and CXCL13 signaling pathways. Analysis of pretreatment RNA-seq data from 48 R/R B-NHL patients confirmed that high Tfh abundance is associated with poor glofitamab response. In PDLS, anti-TIGIT co-treatment enhanced glofitamab efficacy in low responders, and Tfh depletion experiments confirmed that reducing Tfh activity increased B-cell depletion. Together, these findings identify CD8+ T-cell exhaustion and functionally activated Tfh cells as key factors associated with glofitamab resistance in R/R B-NHL. This work supports their potential use as predictive biomarkers for selecting patients with higher probability of response and provides a foundation for future combination therapeutic strategies.
Référence
Blood. 2026 02 26;:
