@article{4e5a35b963314f00a08dc1f5b1c1beb8,
title = "Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy",
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.",
keywords = "Crohn's disease, high-dimensional profiling, inflammatory bowel disease, molecular classification, single-cell RNA sequencing",
author = "Martin, {Jerome C.} and Christie Chang and Gilles Boschetti and Ryan Ungaro and Mamta Giri and Grout, {John A.} and Kyle Gettler and Chuang, {Ling shiang} and Shikha Nayar and Greenstein, {Alexander J.} and Marla Dubinsky and Laura Walker and Andrew Leader and Fine, {Jay S.} and Whitehurst, {Charles E.} and Mbow, {M. Lamine} and Subra Kugathasan and Denson, {Lee A.} and Hyams, {Jeffrey S.} and Friedman, {Joshua R.} and Desai, {Prerak T.} and Ko, {Huaibin M.} and Ilaria Laface and Guray Akturk and Schadt, {Eric E.} and Helene Salmon and Sacha Gnjatic and Rahman, {Adeeb H.} and Miriam Merad and Cho, {Judy H.} and Ephraim Kenigsberg",
note = "Funding Information: The authors would like to thank the patients who participated in the study. The authors would like to warmly thank Dr. Jean-Frederic Colombel (co-director of the Feinstein IBD Center, Mount Sinai Hospital, New York, NY) for invaluable discussions and insights on Crohn{\textquoteright}s disease. The authors would also like to thank Dr. Emilie Grasset (Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY) for critical insights on B cells analysis. We thank Dr. Andrew Chess for fruitful discussions. 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. Funding Information: The authors would like to thank the patients who participated in the study. The authors would like to warmly thank Dr. Jean-Frederic Colombel (co-director of the Feinstein IBD Center, Mount Sinai Hospital, New York, NY) for invaluable discussions and insights on Crohn's disease. The authors would also like to thank Dr. Emilie Grasset (Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY) for critical insights on B cells analysis. We thank Dr. Andrew Chess for fruitful discussions. 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. Conceptualization, J.C.M. E.K. J.H.C. and M.M.; Methodology, J.C.M. G.B. E.K. G.A. H.S. S.G. and A.H.R.; Software, E.K.; Formal Analysis, E.K.; Investigation, J.C.M. G.B. C.C. M.G. J.A.G. L.W. A.L. H.M.K. and I.L.; Data Curation, M.G. K.G. and R.U.; Resources, L.-S.C. S.N. A.J.G. M.D. J.S.F. C.E.W. M.L.M. S.K. L.A.D. J.S.H. J.R.F. P.T.D. H.M.K. E.S.S. S.G. and A.H.R.; Writing – Original Draft, J.C.M. E.K. and M.M.; Writing – Review & Editing, J.C.M. C.W.E. J.H.C. E.K. M.M. and J.R.F.; Visualization, J.C.M. C.C. G.A. and E.K.; Supervision, J.C.M. M.M. J.H.C. and E.K.; Funding Acquisition, J.H.C. and M.M. This study was funded partially by a Grant from Boerhinger Ingelheim to M.M. R.U. has served as an advisory board member or consultant for Janssen, Pfizer, and Takeda and received research grants from Abbvie, Boehringer Ingelheim, and Pfizer. S.G. reports receiving commercial research funding from Immune Design, Pfizer, Janssen R&D, Genentech, Regeneron, and Bristol-Myers Squibb and is a consultant/advisory board member for Merck, OncoMed, Neon Therapeutics, and B4CC. L.A.D. has received grant support from Janssen. Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = sep,
day = "5",
doi = "10.1016/j.cell.2019.08.008",
language = "English",
volume = "178",
pages = "1493--1508.e20",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}