Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy
Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy
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DOI：
10.1016/j.cell.2019.08.008
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发表时间：
2019-09-05
期刊：
影响因子：
64.5
通讯作者：
Kenigsberg, Ephraim
中科院分区：
文献类型：
--
作者：
Martin, Jerome C.;Chang, Christie;Kenigsberg, Ephraim
回肠克罗恩病（iCD）中细胞因子阻断的临床获益仅限于一部分患者。在这里，我们将单细胞技术应用于iCD病变，以解决细胞异质性是否有助于治疗抗性。我们发现，一部分患者在炎症组织中表达了一种独特的细胞模块，由IgG浆细胞、炎症单核吞噬细胞、活化T细胞和基质细胞组成，我们将其命名为GIMATS模块。配体-受体相互作用对的分析确定了可能驱动GIMATS模块的独特网络连接。引人注目的是，GIMATS模块也存在于4个独立iCD队列（n = 441）的患者亚组中，其在诊断时的存在与抗TNF治疗后未能实现持久的无皮质类固醇缓解相关。这些结果强调了当前诊断分析的局限性和单细胞作图工具识别治疗反应的新生物标志物和定制治疗机会的潜力。
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.