Altered Interactions between Circulating and Tissue-Resident CD8 T Cells with the Colonic Mucosa Define Checkpoint Inhibitor Colitis

Therapeutic immune checkpoint blockade has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). To define molecular drivers of irColitis, we profiled ~300,000 cells from the colonic mucosa and blood of 29 patients and controls. Patients with irColitis showed expanded mucosal Tregs (regulatory T cells), CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs, and recirculating ITGB2 CD8 T cells. Cytotoxic CD4 T cells, recirculating CD8 T cells, and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 compared to in the presence of anti-PD-1 therapy. Luminal epithelial cells in irColitis patients expressed PCSK9, PD-L1, and interferon-induced signatures associated with apoptosis, increased cell turnover, and malabsorption.Raw data files from both colon and PBMCs from irColitis patients and controls have been provided to dbGaP. Count matrices derived from raw RNA-Seq data will be available through GEO accession GSE206301.]]>

治疗性免疫检查点阻断疗法已彻底革新了肿瘤学领域，但该疗法的应用仍受限于免疫相关不良事件，其中包括免疫检查点抑制剂相关性结肠炎（irColitis）。为明确irColitis的分子驱动机制，我们对29名患者及对照个体的结肠黏膜与血液中的约30万个细胞开展了表征分析。irColitis患者的黏膜调节性T细胞（Tregs，regulatory T cells）、表达CXCL13与Th17基因程序的CD8组织驻留记忆T细胞，以及循环性ITGB2阳性CD8 T细胞均出现扩增。与仅接受抗PD-1治疗的患者相比，接受抗PD-1/CTLA-4联合治疗的结肠炎患者体内，细胞毒性CD4 T细胞、循环性CD8 T细胞以及表达缺氧基因程序的内皮细胞进一步扩增。irColitis患者的腔面上皮细胞可表达PCSK9、PD-L1，并呈现与细胞凋亡、细胞更新增强及吸收不良相关的干扰素诱导特征。来自irColitis患者及对照个体的结肠样本与外周血单个核细胞（PBMCs，peripheral blood mononuclear cells）的原始数据文件已提交至基因型和表型数据库（dbGaP，Database of Genotypes and Phenotypes）。由原始RNA测序数据衍生得到的计数矩阵将通过基因表达汇编（GEO，Gene Expression Omnibus）登录号GSE206301对外公开。