folder

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

Authors

  • V. Horn
  • C.A. Cancino
  • L.M. Steinheuer
  • B. Obermayer
  • K. Fritz
  • A.L. Nguyen
  • K.S. Juhran
  • C. Plattner
  • D. Bösel
  • L. Oldenburg
  • M. Burns
  • A.R. Schulz
  • M. Saliutina
  • E. Mantzivi
  • D. Lissner
  • T. Conrad
  • M.F. Mashreghi
  • S. Zundler
  • E. Sonnenberg
  • M. Schumann
  • L.M. Haag
  • D. Beule
  • L. Flatz
  • Z. Trjanoski
  • G. D'Haens
  • C. Weidinger
  • H.E. Mei
  • B. Siegmund
  • K. Thurley
  • A.N. Hegazy

Journal

  • Gastroenterology

Citation

  • Gastroenterology 168 (2): 327-343

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.


DOI

doi:10.1053/j.gastro.2024.09.021