ABSTRACT
Ulcerative colitis (UC) is an inflammatory intestinal disorder driven by mucosal immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin monoclonal antibody that is effective for treating UC. VDZ is thought to primarily inhibit lymphocyte trafficking to the intestine, but its effect on other cell subsets is less well characterized. To identify the inflammatory cells that contribute to colitis and respond to VDZ, we performed a single-cell transcriptomic and proteomic analysis of peripheral blood and colonic biopsies in healthy controls (HC) and patients with UC on either aminosalicylates or VDZ. We identified mononuclear phagocytes (MNPs) as a primary target of VDZ, with comparatively modest effects on lymphocytes. Spatial proteomics and transcriptomics demonstrated increased density and proximity of MNP and fibroblast subsets in UC biopsies when compared to HC, with inhibition by VDZ. VDZ non-responders were enriched for activated fibroblast and MNP signatures in a validation cohort.
Competing Interest Statement
S. Lewin has received research support from Takeda. N. El-Nachef is a consultant for Ferring, Federation Bio Grant and receives funding from Finch Therapeutics, Seres, Freenome, and Assembly Biosciences. U. Mahadevan serves as a consultant for Abbvie, BMS, Boeringher Ingelheim, Gilead, Janssen, Lilly, Pfizer, Prometheus biosciences, Protagonist, Rani Therapeutics, Surrozen, and Takeda. D. Oh has received research support from Merck, PACT Pharma, the Parker Institute for Cancer Immunotherapy, Poseida Therapeutics, TCR2 Therapeutics, Roche/Genentech, and Nutcracker Therapeutics, and travel/accommodations from Roche/Genentech. The Combes lab has received research support from Eli Lilly and Genentech and A. Combes consults for Foundery Innovations. The Kattah lab receives research support from Eli Lilly. M. Kattah is a consultant for Sonoma Biotherapeutics.
