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

Jerome C Martin1, Christie Chang1, Gilles Boschetti1

  • 1Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Cell
|September 3, 2019
PubMed

Insights

A specific cellular module, GIMATS, in ileal Crohn's disease (iCD) lesions predicts poor response to anti-TNF therapy. Identifying this module may improve treatment strategies for Crohn's disease patients.

Area of Science:

  • Gastroenterology
  • Immunology
  • Cell Biology

Background:

  • Cytokine blockade offers limited clinical benefit in ileal Crohn's disease (iCD).
  • Cellular heterogeneity in inflamed tissues may contribute to treatment resistance.
  • Current diagnostic assays lack precision for predicting treatment response.

Purpose of the Study:

  • To investigate whether cellular heterogeneity in iCD lesions contributes to resistance against cytokine blockade therapy.
  • To identify novel cellular signatures associated with treatment resistance in iCD.
  • To explore the potential of single-cell mapping for identifying biomarkers of treatment response.

Main Methods:

  • Application of single-cell technologies to iCD lesions.
  • Analysis of ligand-receptor interaction pairs to understand cellular network connectivity.
  • Validation of identified cellular modules across multiple independent iCD cohorts.

Main Results:

  • A distinct cellular module, termed GIMATS (IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells), was identified in a subset of iCD patients.
  • The GIMATS module exhibited unique network connectivity driven by specific ligand-receptor interactions.
  • Presence of the GIMATS module at diagnosis correlated with failure to achieve durable corticosteroid-free remission with anti-TNF therapy in four independent cohorts (n=441).

Conclusions:

  • Cellular heterogeneity, exemplified by the GIMATS module, plays a significant role in treatment resistance in iCD.
  • The GIMATS module serves as a potential biomarker for predicting poor response to anti-TNF therapy.
  • Single-cell mapping technologies offer promise for discovering novel biomarkers and enabling personalized therapeutic strategies for iCD.
Keywords:
Crohn’s diseasehigh-dimensional profilinginflammatory bowel diseasemolecular classificationsingle-cell RNA sequencing

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