Beta-Catenin Mutations Can Impact on the Interplay Between Tumor and Immune Cells and Hepatic Microbiota in Hepatocellular Cancer.

INTRODUCTION: Emerging evidence links alterations in the tumor microbiome to therapeutic responses to immunotherapy. Alterations in β-catenin are among the most frequently observed oncogenic drivers of hepatocarcinogenesis and are associated with T-cell exclusion. However, their effect on the immune cell environment and microbiome in hepatocellular cancer is not well understood. We hypothesized that β-catenin could modulate the immune microenvironment through alterations in the secretome and release of extracellular vesicles (EV) that mediate tumor and immune cell interactions and increase tumor growth within regions with attenuated immune activity and reduced microbial diversity. METHODS: We used a synthetic transgenic murine model of β-catenin-driven hepatocarcinogenesis to analyze microbiome composition, diversity, and immune cell profiles in vivo. Tumor and stool samples were collected from mice with early- or late-stage hepatocellular carcinoma and were used for profiling. RESULTS: The microbiome associated with intrahepatic tumors differs from that in non-tumoral regions, normal liver tissues, and gut tissues. Constitutive β-catenin expression modulates lipopolysaccharide-mediated signaling in macrophages and alters the secretion of immunomodulatory chemokines and cytokines. Tumoral immune cell profiles differed from those in hepatic tissues. EV-mediated signaling between immune cells and epithelial cells with mutant β-catenin and immune cells modulates immune cell populations in vitro and in vivo. CONCLUSION: Mutations in β-catenin can drive immune responses through EV-based tumor cell-immune cell interactions to modulate both the tumor microflora and immune microenvironment. A potential strategy to augment responses to immunotherapy for hepatocellular cancer could target these interactions to restore microbial diversity or immune cell infiltration within the tumor microenvironment.