Distinct immune microenvironment of venous tumor thrombus in hepatocellular carcinoma at single-cell resolution

肝细胞癌 免疫系统 癌症研究 医学 肿瘤微环境 CD8型 转移 免疫学 内科学 癌症
作者
Kaiqian Zhou,Yucheng Zhong,Ming-Fang Song,Yun‐Fan Sun,Wei Zhu,Jianwen Cheng,Yang Xu,Zefan Zhang,Pengxiang Wang,Zheng Tang,Jian Zhou,Liye Zhang,Jia Fan,Xin‐Rong Yang
出处
期刊:Hepatology [Lippincott Williams & Wilkins]
标识
DOI:10.1097/hep.0000000000001182
摘要

Portal vein tumor thrombus (PVTT) worsens the prognosis of hepatocellular carcinoma by increasing intrahepatic dissemination and inducing portal vein hypertension. However, the immune characteristics of PVTT remain unclear. Therefore, this study aims to explore the immune microenvironment in PVTT. Time-of-flight mass cytometry (CyTOF) revealed that macrophages and monocytes were the dominant immune cell type in PVTT, with a higher proportion than in primary tumor (PT) and blood (54.1% vs. 26.3% and 9.1%, p<0.05). The differentially enriched clustering of inhibitory and regulatory immune cells in PVTT indicated an immune-suppressive environment. According to the single-cell RNA sequencing (scRNA-seq), TAM-C5AR1 was characterized by leukocyte chemotaxis and was the most common subpopulation in PVTT (36.7%). Multiple immunofluorescence staining showed that the C5aR+ TAM/Mφ were enriched in PVTT compared to both PT and liver, and positively correlated with C5a (r=0.559, p<0.001). Notably, THP-1 (monocyte cell line) was recruited by CSQT2 (PVTT cell line) and exhibited up-regulation of CD163, CD206, and PD-L1 upon stimulation. C5aR antagonist could reverse this. C5aR+ TAMs could also inhibit Granzyme B in CD8+ T cells. High infiltration of C5aR+ TAMs in PVTT correlated with poor differentiation (p<0.009), and was a risk factor for overall survival (p=0.003) and for re-formation of PVTT after resection (p=0.007). TAMs, especially C5aR+ TAMs, were enriched in PVTT. C5aR+ TAMs contribute to the development of PVTT and poor prognosis by reshaping the immunosuppressive environment.
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