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Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy

Jerome C. Martin, Christie Chang, Gilles Boschetti, Ryan Ungaro, Mamta Giri, John A. Grout, Kyle Gettler, Ling-shiang Chuang, Shikha Nayar, Alexander J. Greenstein, Marla Dubinsky, Laura Walker, Andrew Leader, Jay S. Fine, Charles E. Whitehurst, M Lamine Mbow, Subra Kugathasan, Lee A. Denson, Jeffrey S. Hyams, Joshua R. Friedman, Prerak T. Desai, Huaibin M. Ko, Ilaria Laface, Guray Akturk, Eric E. Schadt, Helene Salmon, Sacha Gnjatic, Adeeb H. Rahman, Miriam Merad, Judy H. Cho, Ephraim Kenigsberg

Clinical benefits of cytokine blockade in ileal Crohn’s disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n = 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.

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Species: human
Number of cells: 82133
Number of downloads: 143
Study size: 699MB
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