Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
Front Immunol. 2022 Apr 26;13:871769. doi: 10.3389/fimmu.2022.871769. eCollection 2022.
To dissect the tumor ecosystem following immune checkpoint blockades (ICBs) in intrahepatic cholangiocarcinoma (ICC) at a single-cell level.
Single-cell RNA sequencing (scRNA-seq) data of 10 ICC patients for the ICB clinical trial were extracted from GSE125449 and systematically reanalyzed. Bulk RNA-seq data of 255 ICC patients were analyzed. Infiltration levels of SPP1CD68 tumor-associated macrophages (TAMs) were examined by dual immunofluorescence (IF) staining in 264 resected ICC samples. The correlation between SPP1 TAMs and clinicopathological features as well as their prognostic significance was evaluated.
Among the 10 patients, five received biopsy at baseline, and others were biopsied at different timings following ICBs. Single-cell transcriptomes for 5,931 cells were obtained. A tighter cellular communication network was observed in ICB-treated ICC. We found a newly emerging VEGF signaling mediated by PGF-VEGFR1 between cancer-associated fibroblasts (CAFs) and endothelial cells in ICC following ICBs. SPP1 expression was dramatically upregulated, and SPP1 TAM gene signatures were enriched in TAMs receiving ICB therapy. We also identified SPP1 TAMs as an independent adverse prognostic indicator for survival in ICC.
Our analyses provide an overview of the altered tumor ecosystem in ICC treated with ICBs and highlight the potential role of targeting CAFs and SPP1TAMs in developing a more rational checkpoint blockade-based therapy for ICC.
在单细胞水平上剖析免疫检查点阻断（ICB）后肝内胆管癌（ICC）的肿瘤生态系统。
从 GSE125449 中提取了 10 名接受 ICB 临床试验的 ICC 患者的单细胞 RNA 测序（scRNA-seq）数据，并进行了系统的重新分析。分析了 255 名 ICC 患者的批量 RNA-seq 数据。在 264 个切除的 ICC 样本中通过双重免疫荧光（IF）染色检查 SPP1CD68 肿瘤相关巨噬细胞（TAMs）的浸润水平。评估了 SPP1 TAMs 与临床病理特征的相关性及其预后意义。
在 10 名患者中，5 名在基线时接受了活检，其他患者在接受 ICB 后不同时间进行了活检。获得了 5931 个细胞的单细胞转录组。在接受 ICB 治疗的 ICC 中，观察到更紧密的细胞通讯网络。我们发现了一个新出现的 VEGF 信号，它是由 ICC 中癌症相关成纤维细胞（CAFs）和内皮细胞之间的 PGF-VEGFR1 介导的。SPP1 的表达显著上调，并且 SPP1 TAM 基因特征在接受 ICB 治疗的 TAMs 中富集。我们还确定 SPP1 TAMs 是 ICC 生存的独立不良预后指标。
我们的分析提供了 ICB 治疗的 ICC 中改变的肿瘤生态系统的概述，并强调了靶向 CAFs 和 SPP1TAMs 在开发更合理的基于检查点阻断的 ICC 治疗中的潜在作用。
