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Cholestasis-induced neutrophil phenotypic transformation contributes to the immune escape of colorectal liver metastasis

ABSTRACT: Cholestasis, a serious complication of liver metastasis (LM), contributes to dismal prognosis in patients with colorectal cancer and LM. However, the mechanism underlying the effect of cholestasis on the development of LM or pre-metastatic microenvironment in the liver remains elusive. In this study, we discovered that cholestasis accelerated the progression of LM and is associated with increased neutrophil infiltration, T-cell exclusion, and exhaustion. Besides, Tβ-MCA and GCA promoted the expression of Arg1 and iNOS in neutrophils via the p38/MAPK signaling pathway. The significant suppression of the activation and cytotoxic effects of CD8+ T cells during co-culture with BA-pretreated neutrophils indicated that BAs directly induce the polarization of immunosuppressive neutrophils. Importantly, targeting BA anabolism with Obeticholic acid effectively suppressed the LM of colorectal cancer in a cholestasis mouse model. Our findings suggest that cholestasis, associated with the failure to achieve drainage of primary BAs, accelerates the progression of LM by remodeling the tumor immune microenvironment. Moreover, targeting BA anabolism with OCA may represent a therapeutic strategy for cholestasis-associated LM of colorectal cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE209836 | GEO | 2024/07/10

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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Cholestasis-induced neutrophil phenotypic transformation contributes to the immune escape of colorectal liver metastasis

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