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A Single-Cell Atlas of the Multicellular Ecosystem of Primary and Metastatic Hepatocellular Carcinoma

ABSTRACT: Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment and tumor development. Here, we generated > 70,000 single-cell transcriptomes for 10 HCC patients from four relevant sites: primary tumor, portal vein tumor thrombus (PVTT), metastatic lymph node and non-tumor liver. We discovered a cluster of antitumor central memory T cells enriched in intratumoral tertiary lymphoid structures (TLSs) of HCC. We found chronic HBV/HCV infection increases the infiltration of CD8+ T cells in tumors but aggravates the exhaustion of tumor-infiltrating lymphocytes. We identified MMP9+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and two distinct differentiation trajectories are related to their accumulation. We further demonstrated MMP9+ TAMs can promote HCC cells migration, invasion and angiogenesis. Our data also revealed the heterogeneous population of malignant hepatocytes and found they might play multifaceted roles in shaping the immune microenvironment of HCC. Finally, we identified seven TME subtypes of HCC that can predict patient prognosis. Collectively, this large-scale, single-cell atlas deepens our understanding of the ecosystem in primary and metastatic HCCs, might facilitating identification of new immune therapy strategies for this malignancy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149614 | GEO | 2020/04/30

REPOSITORIES: GEO

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A Single-Cell Atlas of the Multicellular Ecosystem of Primary and Metastatic Hepatocellular Carcinoma

Project description:Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. Here, we generated a single-cell atlas of the multicellular ecosystem of HCCs from four relevant sites. Antitumor central memory T (TCM) cells were found in tertiary lymphoid structures (TLSs). Chronic HBV/HCV infection increases infiltration of CD8+ T cells in tumors but aggravates T cell exhaustion. We identified CD11b+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and two distinct differentiation trajectories contribute to their accumulation. We further demonstrated CD11b+ TAMs promote HCC cells invasion and migration, and angiogenesis. We characterized the heterogeneous subpopulations of malignant hepatocytes and their multifaceted roles in shaping the immune microenvironment. Finally, we identified seven TME subtypes that can predict patient prognosis. Collectively, this large-scale atlas deepens our understanding of the ecosystem in primary and metastatic HCCs, might facilitating the development of new immune therapy strategies for this malignancy.

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The gene expression of HCC cells and HCC cells knocked down TMED3

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