Farnesoid X Receptor Mediates Tumor Immune Evasion by Targeting PD-L1 Induced by a Novel Bile Acid in Hepatocellular Carcinoma

Background: Emerging evidence indicates that bile acids (BAs) play pivotal roles in hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), the receptor of BAs, is considered to be a regulator of the immune response and inflammation in various diseases. However, the relevance of the immune microenvironment to FXR in HCC is unknown. Methods: Flow cytometry analyses were performed to measure the apoptosis rates of HCC cells and the immune checkpoint changes of immune cells. Kaplan-Meier analysis with log-rank test for assessing overall survival and time to recurrence was performed. Exosomes were isolated and cocultured with CD4+ T and CD8+ T cells for functional assays. HCC models were established in a gene-deficient mouse strain to evaluate FXR capability. Findings: We identified a previously unrecognized protumorigenic bile acid subset, Norcholic acid (NorCA). Mechanistic studies suggested that NorCA promotes tumorigenesis and the development of HCC cells by regulating the FXR-SHP-PD-L1 axis. Moreover, tumor-derived Exos formed by NorCA induction affected the immune microenvironment by regulating CD4+ T cells. In addition, we identified a subgroup of FXRlowPD-L1high patients, who have a poor prognosis. Furthermore, a drug combination study demonstrated that the FXR agonist (GW4064) exerted synergistic effects with an anti‐PD‐1 antibody (Ab) in a mouse model. Interpretation: Our results identify a novel protumorigenic bile acid subset demonstrates the immune function of FXR in HCC cells, offering valuable evidence for using FXR agonists combined with an anti‐PD‐1 Ab in combating HCC. Funding: Research supported by grants from fifteen funds. All sources of funding were declared at the end of the text. Declaration of Interest: None potential conflicts of interest were disclosed. Ethical Approval: This study was approved by the Ethics Review Board of the Third Affiliated Hospital, Sun Yat-sen University. Huh-7, LM3, and Hepa1-6 cells were obtained from ATCC