Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing

Abstract

Background/Aims: Hepatocellular carcinoma (HCC), accounting for 75-85% of primary liver cancer cases, is the third leading cause of cancer-related death worldwide. The purpose of this research was to examine the tumor immune microenvironment (TIME) in HCC. Methods: We investigated the HCC TIME by integrated analysis of single-cell and bulk-tissue sequencing data to reveal the landscape of major immune cell types. Results: Regulatory T(Treg) cells were found to be specifically distributed in the TIME of HCC. Several immune checkpoints, including TNFRSF4, TIGIT and CTLA4, were found to be uniquely overexpressed in Treg cells, and the glycolysis/gluconeogenesis pathway was enriched in Treg cells. We also discovered the presence of two NK-cell subsets with different cytotoxic capacities, one in an activated state with antitumor effects and another with an exhausted status. In addition, memory B cells in HCC were found to exist in a unique state, with high proliferation, low differentiation, and low activity, which was induced by overexpression of PRAP1 and activation of the MIF-CD74 axis. Conclusions: We revealed the TIME landscape in HCC, highlighting the heterogeneity of major immune cell types and their potential mechanisms in the formation of an immunosuppressive environment. Hence, blocking the formation of the TIME could be a useful therapeutic strategy for HCC.