Multimodal Profiling of Peripheral Blood Identifies Proliferating Circulating Effector CD4+ T Cells as Predictors for Response to Integrin α4β7–Blocking Therapy in Inflammatory Bowel Disease
Veronika Horn, C Cancino, Lisa M Steinheuer, Benedikt Obermayer, Konstantin Fritz, Anke L. Nguyen, K S Juhran, Christina Plattner, Diana Bösel, Lotte Oldenburg, Marie E. Burns, Axel Schulz, Mariia Saliutina, Eleni Mantzivi, Donata Lissner, Thomas Conrad, Mir‐Farzin Mashreghi, Sebastian Zundler, Elena Sonnenberg, Michael Schümann, Lea-Maxie Haag, Dieter Beule, Lukas Flatz, Imke Atreya, Raja Atreya, Petra Bacher, Christoph Becker, Christian Bojarski, Nathalie Britzen-Laurent, Caroline Bosch-Voskens, Hyun-Dong Chang, Andreas Diefenbach, Claudia Günther, Ahmed N. Hegazy, Ahmed N. Hegazy, Kai Hildner, Christoph S.N. Klose, Kristina Koop, Susanne Krug, Anja A. Kühl, Moritz Leppkes, Rocío López-Posadas, Leif S-H. Ludwig, Clemens Neufert, Markus Neurath, Jay Patankar, Magdalena Prüß, Andreas Radbruch, Chiara Romagnani, Francesca Ronchi, Ashley Sanders, Alexander Scheffold, Jörg-Dieter Schulzke, Michael Schumann, Sebastian Schürmann, Britta Siegmund, Michael Stürzl, Zlatko Trajanoski, Antigoni Triantafyllopoulou, Maximilian Waldner, Carl Weidinger, Stefan Wirtz, Sebastian Zundler, Zlatko Trajanoski, Geert D’Haens, Carl Weidinger, Henrik E. Mei, Britta Siegmund, Kevin Thurley, Ahmed N. Hegazy, Ahmed N. Hegazy
Abstract
Background & Aims Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response. Methods In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell B and T cell receptor sequencing (BCR/TCR-seq); serum proteomics; and multiparametric flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response. Results Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4 + memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4 + memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab. Conclusions These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management.