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, ITGAE^Hi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2^Hi CD8 T cells. Cytotoxic GNLY^Hi CD4 T cells, recirculating ITGB2^Hi 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.

免疫检查点抑制剂 (ICI) 疗法彻底改变了肿瘤学，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)。人们对结肠炎的致病机制知之甚少，结肠炎在小鼠等模型生物体中不易发生。为了确定 irColitis 的分子驱动因素，我们使用单细胞多组学分析了 13 名患有 irColitis 的癌症患者的结肠粘膜和血液中的约 300,000 个细胞（其中 9 名接受抗 PD-1 或​​抗 CTLA-4 单一疗法， 4 名接受双重 ICI 治疗的患者；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。 irColitis 患者表现出粘膜 Tregs 扩张、ITGAE ^Hi CD8 组织驻留记忆 T 细胞表达CXCL13和 Th17 基因程序以及再循环ITGB2 ^Hi 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GNLY ^Hi CD4 T 细胞、再循环ITGB2 ^Hi CD8 T 细胞和表达缺氧基因程序的内皮细胞进一步扩大。 irColitis 患者的管腔上皮细胞表达 PCSK9、PD-L1 和干扰素诱导的与细胞凋亡、细胞更新增加和吸收不良相关的特征。总之，这些数据表明循环 T 细胞和上皮免疫串扰对 PD-1/CTLA-4 依赖性耐受和屏障功能至关重要，并确定了结肠炎的潜在治疗靶点。