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

Abstract

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 M0Hi and M2Hi subtypes. M2Hi ( P = .038) and M0Hi ( P = .018) were independently prognostic for OS on multivariable analysis. Kaplan-Meier estimates demonstrated that patients in M0Hi and M2Hi treated with sorafenib had decreased OS ( P = .041), and angiogenesis hallmark genes were enriched in the M0Hi group. CXCL6 and POSTN were overexpressed in both the M0Hi and the PD-1Hi/PD-L1Hi 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.

LRMP Associates With Immune Infiltrates and Acts as a Prognostic Biomarker in Lung Adenocarcinoma

“…CD8 + T cells are involved in the killing of tumor cells (Sasidharan Nair and Elkord, 2018). Increased M0 macrophage composition is associated with a poorer prognosis in patients with cancer (Farha et al, 2020;Jairath et al, 2020). These data indicated that LUAD with high expression of LRMP may have a higher level of anti-tumor immune cell infiltration and a more positive tumor immune microenvironment.…”

A CIBERSORTx-based immune cell scoring system could independently predict the prognosis of patients with myelodysplastic syndromes

“…While the enrichment of unpolarized M0 macrophages in the tumor microenvironment has been demonstrated to be detrimental for survival of patients with hepatocellular carcinoma and sarcoma 16,40 , their role in MDS and other hematologic malignancies has been scarcely reported.…”

“…It has been shown to outperform other methods in estimating the relative proportion of closely related cell types in bulk tumors without physical cell sorting 12,13 . While the utility of CIBERSORT and CIBERSORTx has been validated in multiple tumor types [14][15][16][17] , their applicability in hematological malignancies remains scarce. A study demonstrated higher fraction of M2 macrophage as a predictor of inferior event-free survival (EFS) and overall survival (OS) in patients with acute myeloid leukemia (AML), and identified the macrophage marker CD206 as a novel prognostic indicator in these patients 18 .…”

Immunological significance of alternative splicing prognostic signatures for bladder cancer

“…Treg infiltration is associated with poor prognosis of BLCA [62,63]. M0 macrophages are related to poor prognosis of HCC [64]. M2 macrophages are involved in tumor microangiogenesis in BLCA and are related to tumor stage and invasiveness [65].…”