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.