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

• Published in: Cell Vol. 178; no. 6; pp. 1493 - 1508.e20
• Main Authors: Martin, Jerome C., Chang, Christie, Boschetti, Gilles, Ungaro, Ryan, Giri, Mamta, Grout, John A., Gettler, Kyle, Chuang, Ling-shiang, Nayar, Shikha, Greenstein, Alexander J., Dubinsky, Marla, Walker, Laura, Leader, Andrew, Fine, Jay S., Whitehurst, Charles E., Mbow, M Lamine, Kugathasan, Subra, Denson, Lee A., Hyams, Jeffrey S., Friedman, Joshua R., Desai, Prerak T., Ko, Huaibin M., Laface, Ilaria, Akturk, Guray, Schadt, Eric E., Salmon, Helene, Gnjatic, Sacha, Rahman, Adeeb H., Merad, Miriam, Cho, Judy H., Kenigsberg, Ephraim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.09.2019; Elsevier
• Subjects: biomarkers; blood plasma; Crohn disease; Crohn Disease - immunology; Crohn Disease - pathology; Crohn Disease - therapy; Crohn’s disease; cytokines; Cytokines - immunology; high-dimensional profiling; Humans; immunoglobulin G; Immunotherapy - methods; inflammatory bowel disease; Intestines - pathology; Life Sciences; molecular classification; patients; phagocytes; Phagocytes - pathology; plasma cells; remission; Single-Cell Analysis; single-cell RNA sequencing; stromal cells; Stromal Cells - pathology; T-lymphocytes; T-Lymphocytes - pathology; therapeutics; Tumor Necrosis Factor-alpha - antagonists & inhibitors; single-cell RNA sequencing; inflammatory bowel disease; high-dimensional profiling; molecular classification; Crohn’s disease
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.08.008

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. [Display omitted] •Identification of a cellular module called GIMATS in a subset of CD patients•The GIMATS module refers to IgG PCs, inf. MNPs, and activated T and stromal cells•GIMATS organization is driven by a unique MNP-dependent cytokine/chemokine network•GIMATS associates with failure to achieve durable remission upon anti-TNF therapy Single-cell analysis of inflamed tissues from Crohn’s patients demonstrates the existence of two qualitatively distinct subsets of disease, with distinct responses to anti-TNF therapy.