A monocyte-derived blood transcriptomic signature reveals systemic immunosuppression in HCC and partial reversal following curative therapy

Abstract

Background: Liver ablation or resection can cure early-stage hepatocellular carcinoma (HCC), yet late diagnosis and high relapse rates hinder long-term survival. We sought to delineate how tumor burden-and its removal-reshape the systemic immune transcriptome and extract blood-based signatures with diagnostic and prognostic potential.

Method: Peripheral blood mononuclear cells (PBMCs) from six early-stage HCC patients were subjected to single-cell RNA sequencing (scRNA-seq) both prior to and 1-3 months following curative therapy, alongside six age-matched healthy controls. The data were integrated with independent bulk PBMC transcriptomes and public single-cell datasets of paired tumor and adjacent liver immune cells.

Result: Pre-therapy PBMCs displayed an immunosuppressive transcriptional program characterized by elevated TGF beta signaling and ubiquitin-mediated proteolysis. Curative therapy attenuated these pathways and partially restored interferon responses, cytotoxic gene expression, and intercellular communication, although the values remained below healthy levels. We cross-validated these features in tissue, identifying concordant immunosuppressive signatures in tumor versus adjacent-liver immune cells. An immunosuppressive CD14⁺ monocyte subset that expands in the blood of HCC patients displays a transcriptional program matching an IL-10-rich, M2-like macrophage population in liver tissue. A 23-gene signature from this subset was significantly up-regulated in bulk PBMCs from HCC patients (diagnostic) and associated with poor overall survival in the TCGA-LIHC cohort (prognostic). Among these genes, ABCA1 marked monocytes and macrophages with high TGF beta signaling, accurately reflecting tumor-associated immunosuppression in blood and liver.

Conclusion: Early-stage HCC induces a reversible, systemic immunosuppressive transcriptome captured by a monocyte-derived 23-gene blood signature; tumor removal partially restores this profile within three months. These results highlight the potential of blood-derived monocyte signatures as noninvasive biomarkers of HCC-associated immunosuppression and clinical outcome.

Keywords: ABCA1; CD14⁺ monocyte-derived gene signature; hepatocellular carcinoma; single-cell RNA sequencing; systemic immunosuppression.