Inflammatory Bowel Disease (IBD) is characterized by the persistent trafficking of leukocytes into intestinal tissue. The integrin α4β7 is one of the proteins involved in this process. Its interaction with MAdCAM-1, a protein expressed in the endothelial cells, allows the immune cells to infiltrate the intestine. The anti-integrin α4β7 antibody, vedolizumab, targets the trafficking of immune cells. However, despite its efficacy, a significant number of patients do not respond to this therapy, highlighting an urgent need for biomarkers to predict treatment outcomes. This study aimed to characterize the circulating immune landscape in IBD, define the effects of vedolizumab, and identify pre-treatment predictors of therapeutic non-response to this drug. To achieve this aim, we prospectively sampled two cohorts of patients with IBD receiving the anti-integrin α4β7 treatment. We employed multimodal profiling using mass cytometry, single-cell RNA sequencing, single-cell T cell receptor sequencing (TCR-seq), serum proteomics, and multiparametric flow cytometry to comprehensively assess the immune cellular composition of the peripheral blood of IBD patients and healthy donors. We also evaluated the impact of vedolizumab treatment on the circulating immune landscape and its potential associations with treatment response, integrating these data to build a predictive model for therapy response. Compared to healthy donors, IBD patients exhibited a "recruitment signature" with a significant reduction in circulating immune cells, particularly α4β7-expressing T cells. Vedolizumab treatment reversed this signature by sequestering α4β7+ myeloid and lymphoid cells in the circulation, which was accompanied by an increase in serum pro-inflammatory proteins and elevated T cell receptor (TCR) diversity in memory CD4+ T cells. Through integration of multimodal parameters and machine learning, we identified a pre-treatment signature of elevated circulating, activated (HLA-DR+, CD38+) and proliferative (Ki-67+) CD4+ memory T cells as a robust predictor of non-response to vedolizumab. These cells expressed a pathogenic Th1/Th17 profile and multiple alternative gut-homing receptors, suggesting they can bypass the α4β7 blockade to infiltrate the intestine. This study identifies the pre-treatment frequency of Ki-67+ memory CD4+ T cells in peripheral blood as a promising biomarker for predicting non-response to vedolizumab in IBD patients. The findings suggest that non-responders may have a population of pathogenic T cells capable of using alternative homing pathways. Our work underscores the value of using accessible peripheral blood samples and multi-parameter analysis to advance personalized medicine in IBD management.
Camila Cancino Matamala (Thu,) studied this question.