Multi-omics analyses reveal a distinct tumor microenvironment in microvascular invasion positive hepatocellular carcinoma

Abstract Purpose Microvascular invasion (MVI) is a risk factor for the recurrence and poor prognosis of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying MVI-mediated progression of HCC remain unclear. This study aimed to discuss the background of MVI-positive HCC through multiple approaches. Patients and methods: The cancer genome atlas (TCGA) database analysis, next-generation sequencing (NGS), time-of-flight mass-cytometry (CyTOF), imaging mass cytometry (IMC) and lipidomics were used to analyze the molecular characteristics of MVI-positive HCC. Results Pathway enrichment analysis of TCGA database and NGS showed that the enriched pathways in MVI-positive HCC were significantly involved in the tumor microenvironment (TME) remodeling; moreover, single-sample gene set enrichment (ssGSEA) and xCell analysis indicated that the TME of MVI-positive HCC might be in low immune state. In-depth interrogation of the immune landscapes using CyTOF showed that the ratio of Tregs to CD4 + T cells in MVI-positive HCC was higher than that in MVI-negative HCC. CD4 + T cells, CD8 + T cells, Tregs and tumor-associated macrophages (TAMs) express higher levels of immune exhaustion-related markers in MVI-positive HCC. IMC further showed that in MVI-positive HCC the distance between T cells and CAFs was significantly shortened, and the expression of PD-L1 in T cells was higher. The lipidomics results showed the cholesterol which may cause T cells to be in immune exhaustion was significantly elevated in MVI-positive HCC. Conclusion Through high-dimensional analysis, we found that there was immunosuppression of TME in MVI-positive HCC, which may be the cause of worse prognosis.