A monocyte-derived blood transcriptomic signature reveals systemic immunosuppression in HCC and partial reversal following curative therapy
Zhou L, Alaswad A, Kumthekar A, Machtens D, Xi Y, Costa B, Xu C, Wirth T, Li Y
Erschienen in
Frontiers in Immunology: Volume 16, Page 1717978
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.
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