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Bile acid synthesis impedes tumor-specific T cell responses during liver cancer [RNA-seq1]

ABSTRACT: The tumor's metabolic landscape significantly influences anti-tumor immunity, but it remains unclear how metabolic pathways commonly active in the organ of tumor-origin influence immunosurveillance. This study focused on the liver and identified accumulation of primary conjugated and secondary bile acids (BAs) as metabolic features associated with hepatocellular carcinoma and liver cancer models. Inhibiting conjugated BA synthesis through BAAT-deletion in hepatocytes enhanced tumor-specific T cell responses, reduced growth, and sensitized tumors to immune checkpoint blockade. BAs regulated CD8+ T cells differently; primary BAs like TCDCA induced oxidative stress and secondary BAs like LCA impaired T cell function through ER stress, which was countered by UDCA. Indeed, dietary UDCA provision suppressed tumor progression. These findings demonstrate how manipulating organ-specific metabolites affects antitumor immunity and modifying BA synthesis or dietary intake could enhance immunotherapy in liver cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE279096 | GEO | 2024/10/09

REPOSITORIES: GEO

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Project description:Background and Aims - Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for human diseases, but differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice. Methods - BA-related parameters, hepatic and intestinal gene expression patterns, liver morphology and intestinal barrier function were assessed in male and female Cyp2c70-/- mice and WT controls at different ages. Effects of ursodeoxycholic acid (UDCA) treatment were evaluated in young adult female mice. Results – Cyp2c70-/- mice were completely devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. BA pool size was unaffected in young-adult male but reduced by 40% in female Cyp2c70-/- mice. Interestingly, plasma BAs and transaminases were highest in Cyp2c70-/- mice at weaning and spontaneously decreased with age. Although bile flow and biliary BA secretion were unchanged in young-adult Cyp2c70-/- mice, indicating absence of cholestasis, plasma BA and transaminase levels were still elevated. These young-adult Cyp2c70-/- mice displayed cholangiocyte proliferation, mild portal fibrosis, altered microbiome composition and increased gut permeability. Only the female Cyp2c70-/- mice developed bridging fibrosis with age (7-8 months). UDCA treatment normalized hepatic and intestinal functions and fully restored liver morphology in female Cyp2c70-/- mice. Conclusion – Cyp2c70-/- mice show transient neonatal cholestasis and develop cholangiopathic features which progress to bridging fibrosis in female mice only. These consequences of Cyp2c70-deficiency are fully restored by treatment with UDCA.

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Bile acid synthesis impedes tumor-specific T cell responses during liver cancer [RNA-seq1]

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