High-dimensional single-cell analysis identifies cellular signatures associated with response to vedolizumab therapy in ulcerative colitis

Abstract Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease of the gastrointestinal tract. When conventional therapy fails, patients need biologics such as vedolizumab (VDZ) to manage the disease. While VDZ has shown a compelling efficacy in UC, the rate of primary non-response amounts up to 50%. To uncover cellular and molecular cues that coordinate VDZ (non-)response, we performed single-cell transcriptomics and high-dimensional immunoprofiling of gut mucosal and peripheral blood cells obtained from 25 UC patients before and 14 weeks after the initiation of VDZ therapy. We show that VDZ non-response is not driven by integrins beyond the VDZ-targeted α4β7 that may carry on the influx of leukocytes to the inflamed gut mucosa. Instead, non-response is marked by a distinct cellular signature of highly abundant innate immune cells, which is clearly detectable before the start of VDZ treatment. We furthermore highlight the aberrant functional state of inflammatory monocytes and regulatory T cells in non-responders, which together with inflammatory fibroblasts form a rewired cell-to-cell communication network. This prospective longitudinal study reveals that mucosal inflammatory mechanisms are fundamentally different between responders and non-responders to VDZ, which provides deeper insights and new opportunities for improvement of UC treatment.