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Dissecting Intra-Tumoral Changes Following Immune Checkpoint Blockades in Intrahepatic Cholangiocarcinoma via Single-Cell Analysis

PURPOSE: To dissect the tumor ecosystem following immune checkpoint blockades (ICBs) in intrahepatic cholangiocarcinoma (ICC) at a single-cell level. METHODS: Single-cell RNA sequencing (scRNA-seq) data of 10 ICC patients for the ICB clinical trial were extracted from GSE125449 and systematically re...

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Detalles Bibliográficos
Autores principales: Sun, Bao-Ye, Zhou, Cheng, Guan, Ruo-Yu, Liu, Gao, Yang, Zhang-Fu, Wang, Zhu-Tao, Gan, Wei, Zhou, Jian, Fan, Jia, Yi, Yong, Qiu, Shuang-Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9088915/
https://www.ncbi.nlm.nih.gov/pubmed/35558087
http://dx.doi.org/10.3389/fimmu.2022.871769
Descripción
Sumario:PURPOSE: To dissect the tumor ecosystem following immune checkpoint blockades (ICBs) in intrahepatic cholangiocarcinoma (ICC) at a single-cell level. METHODS: 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 SPP1(+)CD68(+) 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. RESULTS: 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. CONCLUSION: Our analyses provide an overview of the altered tumor ecosystem in ICC treated with ICBs and highlight the potential role of targeting CAFs and SPP1(+)TAMs in developing a more rational checkpoint blockade-based therapy for ICC.