OP05 High-dimensional single-cell analysis identifies cellular signatures associated with response to vedolizumab therapy in ulcerative colitis
Journal of Crohn's and Colitis(2023)
摘要
Abstract Background The unpredictability of response to biological therapy in ulcerative colitis (UC) patients, including vedolizumab (VDZ), an anti-α4β7 integrin antibody, poses a serious challenge for medical care. This study aims to identify the relevant cellular and molecular signatures that mark response to VDZ by combining single-cell transcriptomics (scRNAseq) and high-dimensional flow cytometry (Cytek). Methods Gut biopsies and peripheral blood mononuclear cells (PBMCs) from patients with active UC were collected 2 weeks prior and 14 weeks after starting VDZ therapy. Response was evaluated at week 14 based on endoscopy and Physician Global Assessment. Transcriptome profiles of 159.188 and 95.057 high-quality single cells were generated from biopsies and PBMCs, respectively. Additional 797.670 CD45+ mucosal cells and 900.000 PBMCs were processed for validating scRNAseq results by Cytek. Results From a total of 25 UC patients (mean age 41±12.7 years, 52% female, 36% anti-TNFα naive), 15 patients (60%) reached response at week 14. Patients with no prior use of anti-TNFα were more likely to achieve remission with VDZ compared to anti-TNFα exposed patients (89% vs 44% response rate, respectively). Analysis of cell abundances revealed a partial recovery of the epithelial and stromal cell mucosal compartments in responders at week 14. Both scRNAseq and Cytek show that in responders VDZ prevented T cells (CD8+IL17+ and CD4+PD1+ subsets) and innate immune cells (NKs, DCs and inflammatory monocytes) from entering mucosa, resulting in their enrichment in PBMCs. In contrast, non-response to VDZ was marked by an expansion of inflammatory fibroblasts and activated endothelial cells, and depletion of most epithelial subsets. VDZ retained CD4 T cells in PBMCs in non-responders, but failed to halt active mucosal inflammation at week 14. Strikingly, involvement of the innate immune cells in UC inflammation prior to VDZ treatment was much more prominent in non-responders who showed higher baseline abundance of NKs, ILCs, γδ-T cells, DCs and inflammatory monocytes in their peripheral blood and mucosa compared to responders. While VDZ inhibited integrin β7 expression on circulating T cells in all patients, only in responders it coincided with the lower mucosal abundance of lymphocytes, suggesting that T cells in non-responders might employ alternative, β7-independent trafficking routes. Conclusion This is the largest prospective scRNAseq study addressing the response to biological therapy in UC. We showed that active, innate immune cell-mediated inflammation marks the primary non-response to VDZ that persists prior to and throughout the treatment, accompanied by β7-independent lymphocyte migration.
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关键词
ulcerative colitis,vedolizumab therapy,high-dimensional,single-cell
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