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 -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.