The fibroblast-centered cellular crosstalk in HBV-positive liver cancer revealed by single cell sequencing

Here, we generated full-length single cell transcriptome data for ~9,000 cells from clinical samples of 11 liver cancer patients to delineate cellular relationships of diverse malignant, immune and stromal cells. We identified an immunomodulatory fibroblast population, FAP+CCL19+CCL21+ CAFs, that expressed signatures of fibroblastic reticular cells and was associated with favorable prognosis in hepatocellular carcinoma (HCC). These CAFs exhibited the potential to recruit NK cells and regulate tumor-associated macrophages, and appeared to be regulated by CXCL12+ endothelial cells in tumors through specific ligand-receptor interaction. Further, we uncovered clonal HBV integration events enriched in tumor cells, and trajectory analysis on tumor cells with clonal HBV integration events revealed that hepatoblast-like cells differentiated into a terminal state with high expression of an immune-resistance program. The intercellular crosstalks between CAFs and cancer cells, macrophages, and NK cells, combined with HBV-based lineage tracing, provide a better understanding for functional roles of CAFs in the HCC microenvironment, and the relationship between HBV integration and liver malignancies. Here, we utilized Smart-seq2 protocol to obtain full-length transcriptional profiles of CD45+ and CD45− cells for 11 liver cancer patients from PBMC, adjacent liver and tumor sites. >>> Due to patient privacy concerns, raw sequence data access provided at China Genomic Sequence Archive (GSA) under accession HRA001595 (https://ngdc.cncb.ac.cn/gsa-human/browse/HRA001595) <<<