![]() We further confirmed the cell type annotation by comparing with the well-annotated cell clusters in the Human Cell Landscape (HCL) project (Supplementary Fig. We then annotated the 53 cell clusters with canonical marker genes of major cell types and found they consist of 15 hepatocyte and cholangiocyte clusters, 14 T and natural killer (NK) cell clusters, 14 myeloid cell clusters, 5 B cell clusters, 3 endothelial cell clusters and 2 fibroblast clusters (Fig. The robustness of the clustering was tested by down-sampling and leave-one-patient-out analyses, which showed robust cluster assignments (Supplementary Fig. A total of 53 clusters of cells were identified using a shared-nearest neighbor (SNN)-based unsupervised clustering method (Fig. To generate a landscape of the global cellular microenvironment of primary and metastatic HCCs, we merged the scRNA-seq data across all tissues and patients using a canonical correlation analysis (CCA)-based batch correction approach. Overall, we obtained the transcriptomic data of 71,915 single cells, with an average of 1979 detected genes per cell (Supplementary Data 2). Transcriptomes of single cells were measured in four relevant tissue types of these patients, including the non-tumor liver (NTL), primary tumor (PT), portal vein tumor thrombus (PVTT) and metastatic lymph node (MLN) tissues (Supplementary Fig. To generate a single-cell atlas of the multicellular ecosystem of HCC, we recruited 10 HCC patients with primary and/or metastatic tumors, who are representatives of different tumor-node-metastasis (TNM) stages and hepatitis virus infection status (Supplementary Fig. ScRNA-seq and cell typing of primary and metastatic HCC and paired non-tumor liver tissues This large-scale transcriptomic data of single-cell resolution in HCC can be used as a resource for further exploring the basic characteristics of TME and for developing potentially effective immunotherapy strategies for this malignancy. The intratumoral heterogeneity of malignant hepatocytes and their multifaceted functions in shaping the immune microenvironment are also assessed. Important immune cell subtypes are identified and their relationships with tumor progression are investigated. Here, we perform a large-scale, unbiased assessment of the multicellular ecosystem of primary or metastatic HCCs from multiple tissue types. However, these studies have not characterized a global landscape of TME combining primary and metastatic HCCs. Several pioneering single-cell RNA sequencing (scRNA-seq) studies have investigated the immune cells or malignant cells of primary HCCs 4, 5, 6 and early-relapse HCCs 7. It is, therefore, paramount to characterize the baseline landscape of HCC cellular ecosystem and its key compositions associated with cancer development and immunotherapy. Cancer immunotherapies such as immune checkpoint blockade have dramatically advanced the oncological treatment landscape over the past decades however, the treatment options for HCC are still limited and the response rates remain low 3. HCC is typically resistant to chemotherapy and radiotherapy, and treatment with sorafenib or regorafenib is of limited clinical benefit 2. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and is the third leading cause of cancer deaths 1. Collectively, this large-scale atlas deepens our understanding of the HCC microenvironment, which might facilitate the development of new immune therapy strategies for this malignancy. Finally, we identify seven microenvironment-based subtypes that can predict prognosis of HCC patients. ![]() ![]() We also characterize the heterogeneous subpopulations of malignant hepatocytes and their multifaceted functions in shaping the immune microenvironment of HCC. We find the MMP9 + macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and PPARγ to be the pivotal transcription factor driving their differentiation. We show the enrichment of central memory T cells (T CM) in the early tertiary lymphoid structures (E-TLSs) in HCC and assess the relationships between chronic HBV/HCV infection and T cell infiltration and exhaustion. Here, we generate a single-cell atlas of the multicellular ecosystem of HCC from four tissue sites. Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. ![]()
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