Multi-omics Analysis of Microenvironment Characteristics and Immune Escape Mechanisms of Hepatocellular Carcinoma

The immune environment in primary tumor has a profound impact on immunotherapy. However, the clinical relevance of immune environment in hepatocellular carcinoma (HCC) is largely unknown. Here, the immune profile and its clinical response in HCC were investigated. The gene expression profiles of 569 HCCs from three cohorts (The Cancer Genome Atlas, TCGA, n = 257; Gene Expression Omnibus, GEO, n = 170; International Cancer Genome Consortium, ICGC, n = 142) were used in the current study. Five gene expression subtypes (C1-C5) responsible for global immune genes were identified in HCCs at stage I/II. It was found that subtype C4 was associated with upregulation and subtype C5 was associated with downregulation of immune profiles in most metagenes. Immune-correlation analysis of the five subtypes demonstrated that C3 and C4 had higher immune score and better prognostic outcome, as compared with other subtypes. Moreover, the mutation frequencies of TP53, CTNNB1, and AXIN1 had significant difference in the five subgroups. Further, the expression of PDCD1, CD274, PDCD1LG2, CTLA4, CD86, and CD80 was higher in subtype C4 in comparison with the other subtypes. The WGCNA of immune-related genes in the five subtypes revealed that blue and turquoise modules were positively correlated with subtype C4 and were associated with 12 common pathways in the KEGG database. These results were validated in external cohorts from the NCI (National Cancer Institute) cohort (GSE14520) and the ICGC (International Cancer Genome Consortium) cohort. In summary, one immune-enhanced subtype and one immune-decreased subtype having different immune and clinical characteristics may provide guidance for developing novel treatment strategies for immune system malfunction-related cancer.