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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02895-x

摘要内容如下：

免疫检查点抑制剂（ICI）疗法使肿瘤学发生了革命性的变化，但治疗受到免疫相关不良事件的限制，包括检查点抑制剂结肠炎（Ircolitis）。我们对结肠炎的致病机制知之甚少，因为结肠炎在模式生物（如小鼠）中并不容易发生。为了确定结肠炎的分子驱动因素，我们使用单细胞多组学对13名患有结肠炎的癌症患者（9名接受抗PD-1或抗CTLA-4单药治疗，4名接受双重ICI治疗；大多数患者患有皮肤癌或肺癌）、8名接受ICI治疗的对照患者和8名健康对照患者的结肠粘膜和血液中的约300，000个细胞进行了分析。患有结肠炎的患者表现出扩增的粘膜Tregs、表达CXCL13和Th17基因程序的ITGaehi CD8组织驻留记忆T细胞和再循环的ITGb2hi CD8 T细胞。与抗PD-1治疗相比，抗PD-1/CTLA-4治疗相关的结肠炎中细胞毒性GnLYHI CD4 T细胞、再循环ITGB2HI CD8 T细胞和表达缺氧基因程序的内皮细胞进一步扩增。结肠炎患者的肠腔上皮细胞表达PCSK9、PD-L1和干扰素诱导的信号，这些信号与细胞凋亡、细胞更新增加和吸收不良有关。总之，这些数据提示了循环T细胞和上皮-免疫交叉对PD-1/CTLA-4依赖性耐受和屏障功能的关键作用，并确定了结肠炎的潜在治疗靶点。

英文原文如下：

Abstracts

Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, which does not readily occur in model organisms, such as mice. To define molecular drivers of irColitis, we used single-cell multi-omics to profile approximately 300,000 cells from the colon mucosa and blood of 13 patients with cancer who developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy and four on dual ICI therapy; most patients had skin or lung cancer), eight controls on ICI therapy and eight healthy controls. Patients with irColitis showed expanded mucosal Tregs, ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2Hi CD8 T cells. Cytotoxic GNLYHi CD4 T cells, recirculating ITGB2Hi CD8 T cells and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 therapy compared to anti-PD-1 therapy. Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis.

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