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.

中文翻译：

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追踪检查点诱导结肠炎患者中原位检查点抑制剂结合的靶 T 细胞

检查点抑制剂（CPI）治疗癌症的成功受到包括结肠炎在内的免疫相关不良反应的影响。 CPI 诱导的结肠炎的特点是常驻粘膜 IFNγ 细胞毒性 CD8 T 细胞的扩增，但这些细胞是如何产生的尚不清楚。在这里，我们使用多模式单细胞和亚细胞空间转录组学 (ST) 追踪肠道组织中 CPI 结合的 T 细胞。发炎组织中的靶点占有率增加，药物结合的 T 细胞位于不同的微域中，这些微域以特定的细胞间信号传导和转录梯度为特征。 CPI 结合细胞主要是 CD4 T 细胞，包括 CPI 结合外周辅助细胞、滤泡辅助细胞和调节性 T 细胞的富集。 IFNγ CD8 T 细胞从组织驻留记忆 (TRM) 和外周细胞群中出现，表现出更受限的靶点占据特征，并与缺乏有效调节线索的受损上皮微区共定位。我们的多模式分析确定了因果路径，并构成了为新的预防策略提供信息的资源。