Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; MRC WIMM Centre For Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Cancer Cell. 2024 May 13;42(5):797-814.e15. doi: 10.1016/j.ccell.2024.04.010.
The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8 T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4 T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8 T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.
检查点抑制剂 (CPIs) 在癌症治疗中的成功受到了免疫相关不良反应的影响，包括结肠炎。CPIs 诱导的结肠炎的特征是常驻黏膜 IFNγ 细胞毒性 CD8 T 细胞的扩增，但这些细胞是如何产生的还不清楚。在这里，我们使用多模式单细胞和亚细胞空间转录组学 (ST) 来跟踪肠道组织中的 CPI 结合 T 细胞。在炎症组织中，药物结合的 T 细胞的靶标占有率增加，与特定的细胞间信号和转录梯度区分的特定微区中的药物结合的 T 细胞。CPI 结合的细胞主要是 CD4 T 细胞，包括 CPI 结合的外周辅助性 T 细胞、滤泡辅助性 T 细胞和调节性 T 细胞的富集。IFNγ CD8 T 细胞来源于组织驻留记忆 (TRM) 和外周群体，表现出更受限的靶标占有率谱，并与缺乏有效调节信号的受损上皮微区共定位。我们的多模式分析确定了因果途径，并构成了一个资源，以提供新的预防策略的信息。
