更正：B7-H3 CAR-T 细胞清除肝内胆管癌并诱导持久应答
Correction: B7-H3 CAR T cells eradicate intrahepatic cholangiocarcinoma and induce durable response.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
FXR 介导的抗原特异性 CD8⁺ T 细胞增强肝内胆管癌的抗肿瘤免疫
英文原题：FXR-mediated antigen-specific CD8(+) T cell enhances antitumor immunity in intrahepatic cholangiocarcinoma.
查看英文原题
FXR-mediated antigen-specific CD8(+) T cell enhances antitumor immunity in intrahepatic cholangiocarcinoma.
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研究概要
这些数据表明 FXR 是一种免疫检查点，并支持将 UDCA 重新用于 ICC 免疫治疗。
研究思路结论见上方概要
背景
肝内胆管癌（ICC）可手术切除的机会有限，晚期患者对免疫治疗反应不佳。因此，探索新的治疗策略至关重要。法尼醇X受体（FXR）是一种核受体，近年来有报道称其可调控免疫细胞。然而，FXR能否调控CD8+ T细胞从而影响肿瘤发展仍不清楚。
方法
采用自发性小鼠ICC模型，在全身性Nr1h4敲除小鼠和T细胞特异性条件性敲除小鼠中评估FXR在CD8+ T细胞介导的抗肿瘤免疫中的功能，并通过多色流式细胞术进行免疫表型分析。通过四聚体染色和OT-1 T细胞过继转移追踪肿瘤抗原特异性CD8+ T反应。使用RNA测序、染色质免疫沉淀测序（ChIP-seq）、染色质免疫沉淀聚合酶链反应（ChIP-PCR）和荧光素酶报告基因实验证实FXR的调控机制。在小鼠模型中以及使用患者来源肿瘤片段进行离体实验，通过给予FXR抑制剂熊去氧胆酸（UDCA），分别作为单药治疗和与抗程序性死亡配体1（PD-L1）阻断联合治疗，评估其转化治疗潜力。
结果
FXR在人和小鼠ICC的耗竭CD8+TIL（肿瘤浸润淋巴细胞）中特异性过表达。FXR消融增强了CD8+T细胞的效应功能、增殖和干细胞样祖细胞能力，从而实现有效的肿瘤控制。机制上，FXR通过直接结合LAG3启动子转录上调耗竭标志物LAG3。用UDCA对FXR进行药理学抑制可逆转T细胞耗竭，并与抗PD-L1治疗协同，在鼠模型和人ICC离体培养中显著抑制肿瘤生长并增强肿瘤细胞凋亡。
展开英文摘要原文
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.
论文信息
- 作者
- Liu S、Liang Z、Zhu L、Zheng Y、Yu H、Ye S、Liang T、Huang L
- 第一作者单位
- Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.China
- 通讯作者单位
- Department of Hepatic Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China ye_linsen@163.com yelilinlcmv@tmmu.edu.cn caoyj27@mail.sysu.edu.cn.China
- 期刊
- Journal for immunotherapy of cancer2025 Nov 28
- 原文标识
- PubMed 41314981 · DOI 10.1136/jitc-2025-012259
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