Jin Han, Kim Woonghee, Yuan Meng, Li Xiangyu, Yang Hong, Li Mengzhen, Shi Mengnan, Turkez Hasan, Uhlen Mathias, Zhang Cheng, Mardinoglu Adil
Central Laboratory, Tianjin Medical University General Hospital, Tianjin, China.
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
Front Immunol. 2024 Dec 3;15:1446453. doi: 10.3389/fimmu.2024.1446453. eCollection 2024.
Macrophages and T cells play crucial roles in liver physiology, but their functional diversity in hepatocellular carcinoma (HCC) remains largely unknown.
Two bulk RNA-sequencing (RNA-seq) cohorts for HCC were analyzed using gene co-expression network analysis. Key gene modules and networks were mapped to single-cell RNA-sequencing (scRNA-seq) data of HCC. Cell type fraction of bulk RNA-seq data was estimated by deconvolution approach using single-cell RNA-sequencing data as a reference. Survival analysis was carried out to estimate the prognosis of different immune cell types in bulk RNA-seq cohorts. Cell-cell interaction analysis was performed to identify potential links between immune cell types in HCC.
In this study, we analyzed RNA-seq data from two large-scale HCC cohorts, revealing a major and consensus gene co-expression cluster with significant implications for immunosuppression. Notably, these genes exhibited higher enrichment in liver macrophages than T cells, as confirmed by scRNA-seq data from HCC patients. Integrative analysis of bulk and single-cell RNA-seq data pinpointed macrophages as an unfavorable cell type, while macrophages, macrophages, and T cells were associated with a more favorable prognosis for HCC patients. Subsequent scRNA-seq investigations and experiments elucidated that SPP1, predominantly secreted by macrophages, inhibits T cell proliferation. Finally, targeting SPP1 in tumor-associated macrophages through inhibition led to a shift towards a favorable phenotype.
This study underpins the potential of SPP1 as a translational target in immunotherapy for HCC.
巨噬细胞和T细胞在肝脏生理学中发挥着关键作用，但其在肝细胞癌（HCC）中的功能多样性仍 largely未知。
使用基因共表达网络分析对两个HCC的批量RNA测序（RNA-seq）队列进行分析。关键基因模块和网络被映射到HCC的单细胞RNA测序（scRNA-seq）数据。以单细胞RNA测序数据为参考，通过反卷积方法估计批量RNA-seq数据的细胞类型比例。进行生存分析以评估批量RNA-seq队列中不同免疫细胞类型的预后。进行细胞间相互作用分析以确定HCC中免疫细胞类型之间的潜在联系。
在本研究中，我们分析了来自两个大规模HCC队列的RNA-seq数据，揭示了一个对免疫抑制有重大影响的主要且一致的基因共表达簇。值得注意的是，正如HCC患者的scRNA-seq数据所证实的，这些基因在肝巨噬细胞中的富集程度高于T细胞。批量和单细胞RNA-seq数据的综合分析确定巨噬细胞是一种不利的细胞类型，而巨噬细胞、巨噬细胞和T细胞与HCC患者更有利的预后相关。随后的scRNA-seq研究和实验阐明，主要由巨噬细胞分泌的SPP1抑制T细胞增殖。最后，通过抑制作用靶向肿瘤相关巨噬细胞中的SPP1导致向有利表型的转变。
本研究支持SPP1作为HCC免疫治疗中转化靶点的潜力。
