The role of OSM/OSMRβ axis in shaping the tumor microenvironment favouring MASLD-Related HCC immune evasion.

Abstract Background: Oncostatin M (OSM) has been shown to contribute to metabolic dysfunction-associated steatohepatitis (MASH) progression to hepatocellular carcinoma (HCC). Here we investigated its role in shaping an immunosuppressive tumor microenvironment (TIME) in MASH-HCCs. Approach: OSM role was investigated through combined analyses of MASLD/MASH patients with or without HCC, MASH-related HCCs originating in wild type and hepatocyte-specific OSM receptor-β (hOSMRβ-/-) deficient mice and in vitro experiments performed on liver cancer and immune cell lines. Results: Analysis of OSM-expressing HCC patients with mixed etiology (TCGA-database) revealed a positive correlation between OSM transcripts and those of several TIME markers. A similar pattern was also observed in murine MASH-HCC tumors. hOSMRβ-/- mice had significantly reduced tumor volume and weight without altering macrophage infiltration and OSM production. However, TIME markers transcripts were lower in HCCs from hOSMRβ-/- mice. These effects associated with a lowering in tumor STAT3 phosphorylation and COX-2 activity. Single-cell RNAseq analysis of human HCCs identified malignant hepatocyte as source of CCL15, a cytokine associated with immunosuppression in HCCs. Circulating CCL15 was markedly elevated in either human and rodent MASH-HCCs and significantly reduced by hOSMRβ deletion. Blocking autocrine OSM signaling in HepG2 or Huh7 cells overexpressing OSM reduced STAT3 phosphorylation, CCL15 production and prevented TIME markers expression by co-cultured macrophage-derived THP1 cells. Conclusions: Our findings provide compelling evidence for an autocrine role of OSM/OSMRβ axis in promoting CCL15 production by tumor cells which, in turn, stimulates an immunosuppressive TIME in MASH-HCCs, suggesting OSM as a potential therapeutic target for HCC treatment.