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

• Type of Material: Article
• Authors: Jerome C. Martin, Icahn School of Medicine at Mount Sinai; Christie Chang, Icahn School of Medicine at Mount Sinai; Gilles Boschetti, Icahn School of Medicine at Mount Sinai; Ryan Ungaro, Icahn School of Medicine at Mount Sinai; Mamta Giri, Icahn School of Medicine at Mount Sinai; John A. Grout, Icahn School of Medicine at Mount Sinai; Kyle Gettler, Icahn School of Medicine at Mount Sinai; Ling-shiang Chuang, Icahn School of Medicine at Mount Sinai; Shikha Nayar, Icahn School of Medicine at Mount Sinai; Alexander J. Greenstein, Icahn School of Medicine at Mount Sinai; Marla Dubinsky, Icahn School of Medicine at Mount Sinai; Laura Walker, Icahn School of Medicine at Mount Sinai; Andrew Leader, Icahn School of Medicine at Mount Sinai; Jay S. Fine, Boehringer Ingelheim Pharmaceuticals; Charles E. Whitehurst, Boehringer Ingelheim Pharmaceuticals; M. Lamine Mbow, Boehringer Ingelheim Pharmaceuticals; Subramaniam Kugathasan, Emory University; Lee A. Denson, Cincinnati Childrens Hospital Medical Center; Jeffrey S. Hyams, Connecticut Childrens Medical Center; Joshua R. Friedman, Janssen Research & Development, LLC; Prerak T. Desai, Janssen Research & Development, LLC; Huabin M. Ko, Icahn School of Medicine at Mount Sinai; Ilaria Laface, Icahn School of Medicine at Mount Sinai; Guray Akturk, Icahn School of Medicine at Mount Sinai; Eric E. Schadt, Icahn School of Medicine at Mount Sinai; Helene Salmon, Icahn School of Medicine at Mount Sinai; Sacha Gnjatic, Icahn School of Medicine at Mount Sinai; Adeeb H. Rahman, Icahn School of Medicine at Mount Sinai; Miriam Merad, Icahn School of Medicine at Mount Sinai; Judy H. Cho, Icahn School of Medicine at Mount Sinai; Ephraim Kenigsberg, Icahn School of Medicine at Mount Sinai
• Language: English
• Date: 2019-09-05
• Publisher: Cell Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2019.08.008
• Title of Journal or Parent Work: Cell
• Volume: 178
• Issue: 6
• Start Page: 1493
• End Page: +
• Grant/Funding Information: J.C.M. is supported by “Prix pour les jeunes chercheurs” de la Fondation Bettencourt-Schueller and by the Philippe Foundation; R.U. is supported by a Career Development Award from the Crohn’s and Colitis Foundation and an NIH K23 Career Development Award (K23KD111995–01A1).; J.H.C. is funded by U01 DK062429, U01 DK062422, R01 DK106593, and the Sanford J. Grossman Charitable Trust. M.M. is funded by R56AI137244, U24 AI118644, U19 AI128949, and Boehringer Ingelheim Pharmaceuticals.; This work utilized a mass cytometry instrumentation at the Human Immune Monitoring Center supported by S10 OD023547–01. The work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.
• Keywords: Heterogeneity; Inflamed mucosa; Life Sciences & Biomedicine; Dendritic cells; Maintenance therapy; Biochemistry & Molecular Biology; T-cells; Gene expression; RNA-SEQ; Cell Biology; Science & Technology; Human intestinal macrophages; Innate lymphoid cells; Inflammation
• Research Categories: Biology, Genetics; Biology, Cell; Health Sciences, Oncology; Health Sciences, Immunology

Abstract

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.