FXR-mediated antigen-specific CD8+ T cell enhances antitumor immunity in intrahepatic cholangiocarcinoma.

BACKGROUND

Intrahepatic cholangiocarcinoma (ICC) offers limited opportunities for surgical treatment, and advanced-stage patients exhibit poor responses to immunotherapy. Therefore, the exploration of new therapeutic strategies is of paramount importance. The farnesoid X receptor (FXR) is a nuclear receptor that has been reported to regulate immune cells in recent years. However, whether FXR can regulate CD8+ T cells to affect tumor development remains unknown.

METHODS

The function of FXR in CD8+ T cell-mediated antitumor immunity was assessed using spontaneous murine ICC models in systemic Nr1h4-knockout, and T cell-specific conditional knockout mice, with immune phenotyping performed by multicolor flow cytometry. The tumor antigen-specific CD8+ T response was tracked by tetramer staining and adoptive transfer of OT-1 T cells. The regulatory mechanism of FXR was confirmed using RNA sequencing, Chromatin Immunoprecipitation sequencing (ChIP-seq), Chromatin Immunoprecipitation polymerase chain reaction (ChIP-PCR), and luciferase reporter assays. The translational therapeutic potential was evaluated by administration of the FXR inhibitor ursodeoxycholic acid (UDCA), both as monotherapy and in combination with anti-programmed death-ligand 1 (PD-L1) blockade, in murine models and ex vivo using patient-derived tumor fragments.

RESULTS

FXR was specifically overexpressed in exhausted CD8+ tumor-infiltrating lymphocytes in both human and murine ICC. FXR ablation enhanced CD8+ T-cell effector function, proliferation, and stem-like progenitor capacity, leading to potent tumor control. Mechanistically, FXR transcriptionally upregulated the exhaustion marker LAG3 by directly binding to its promoter. Pharmacological inhibition of FXR with UDCA reversed T-cell exhaustion, and synergized with anti-PD-L1 therapy to significantly suppress tumor growth and enhance tumor cell apoptosis in murine models and human ICC ex vivo cultures.

CONCLUSIONS

Together, these data identify FXR as an immune checkpoint and support repurposing UDCA for ICC immunotherapy.