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The vast majority of hepatocellular carcinoma (HCC) arise in the context of chronic inflammation, especially with hepatitis B or hepatitis C viral infection. Several studies have identified prognostic immune biomarkers in HCC tumors and peritumoral regions. Recently, a Phase 1 trial of a PD-1 inhibitor has demonstrated efficacy in HCC. In order to characterize the diversity of immune microenvironments in HCC, we investigated co-expression networks of immune lineage-specific genes.
We conducted a meta-analysis of gene expression data from over 500 HCC tumors and matched adjacent liver specimens. PD-L1 and PD-L2 had higher RNA levels in adjacent liver, compared with tumors. Tumoral expression of PD-L1 and PD-L2 were correlated with macrophage lineage genes. We identified 3 major co-expression network modules that corresponded with different immune cell sub-types: (1) An infiltrating T cell module was enriched for TCR activation, recruitment chemokines and elevated immune checkpoints. (2) A hepatic stellate cell module was associated with extracellular matrix remodeling, epithelial-to-mesenchymal transition and TGF-beta signaling. (3) A macrophage module had elevated macrophage lineage genes. By integrating these co-expression modules with HCC molecular sub-classes, the infiltrating T cell signature was enriched in the Hoshida S1 subclass1 and Chiang interferon subclass2, and was less prevalent among HCC with CTNNB1 mutations.
Transcriptomic analyses revealed immune cell types and potential regulators in HCC. The joint profiling of infiltrating immune sub-types and genetic alterations may guide the selection of combination therapies.