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

Abstract

Background and aims: Despite the success of biological therapies in treating inflammatory bowel disease (IBD), managing patients remains challenging due to the absence of reliable predictors of therapy response.

Methods: In this study, we prospectively sampled two cohorts of IBD patients receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, serum proteomics, and multidimensional flow cytometry to comprehensively assess vedolizumab-induced immunological 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 non-responders prior to treatment compared with responders. This predictive T cell signature demonstrated an activated Th1/Th17 phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab.

Conclusion: These findings provide a reliable predictive classifier with significant implications for personalized IBD management.

Keywords: CD4(+) memory T cells; Inflammatory bowel disease; cell migration and homing; integrin α4β7; machine learning; single cell profiling; therapy response; vedolizumab.