Characterization of the Tumor Immune Microenvironment Identifies M0 Macrophage-Enriched Cluster as a Poor Prognostic Factor in Hepatocellular Carcinoma

PURPOSE Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and a high recurrence rate. The tumor immune microenvironment in HCC has been characterized as shifted toward immunosuppression. We conducted a genomic data-driven classification of immune microenvironment HCC subtypes. In addition, we demonstrated their prognostic value and suggested a potential therapeutic targeting strategy.METHODS RNA sequencing data from The Cancer Genome Atlas–Liver Hepatocellular Carcinoma was used (n = 366). Abundance of immune cells was imputed using CIBERSORT and visualized using unsupervised hierarchic clustering. Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox regression. Differential expression and gene set enrichment analyses were conducted on immune clusters with poor OS and high programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) coexpression. A scoring metric combining differentially expressed genes and immune cell content was created, and its prognostic value and immune checkpoint blockade response prediction was evaluated.RESULTS Two clusters were characterized by macrophage enrichment, with distinct M0 Hi and M2 Hi subtypes. M2 Hi ( P = .038) and M0 Hi ( P = .018) were independently prognostic for OS on multivariable analysis. Kaplan-Meier estimates demonstrated that patients in M0 Hi and M2 Hi treated with sorafenib had decreased OS ( P = .041), and angiogenesis hallmark genes were enriched in the M0 Hi group. CXCL6 and POSTN were overexpressed in both the M0 Hi and the PD-1 Hi /PD-L1 Hi groups. A score consisting of CXCL6 and POSTN expression and absolute M0 macrophage content was discriminatory for OS (intermediate: hazard ratio [HR], 1.59; P ≤ .001; unfavorable: HR, 2.08; P = .04).CONCLUSION Distinct immune cell clusters with macrophage predominance characterize an aggressive HCC phenotype, defined molecularly by angiogenic gene enrichment and clinically by poor prognosis and sorafenib response. This novel immunogenomic signature may aid in stratification of unresectable patients to receive checkpoint inhibitor and antiangiogenic therapy combinations.