Bile acid synthesis impedes tumor-specific T cell responses during liver cancer [RNA-seq1]

The tumor's metabolic landscape significantly influences anti-tumor immunity, but it remains unclear how metabolic pathways commonly active in the organ of tumor-origin influence immunosurveillance. This study focused on the liver and identified accumulation of primary conjugated and secondary bile acids (BAs) as metabolic features associated with hepatocellular carcinoma and liver cancer models. Inhibiting conjugated BA synthesis through BAAT-deletion in hepatocytes enhanced tumor-specific T cell responses, reduced growth, and sensitized tumors to immune checkpoint blockade. BAs regulated CD8+ T cells differently; primary BAs like TCDCA induced oxidative stress and secondary BAs like LCA impaired T cell function through ER stress, which was countered by UDCA. Indeed, dietary UDCA provision suppressed tumor progression. These findings demonstrate how manipulating organ-specific metabolites affects antitumor immunity and modifying BA synthesis or dietary intake could enhance immunotherapy in liver cancer. Overall design: To investigate the effect of bile acid treatment on T Cell gene expression. Gene expression profiling analysis using data obtained from RNA-seq of T Cells treated with different bile acids.in vitro activated CD8+ T cells were exposed with different bile acids for 24 hours following with RNA was isolated using Qiagen RNA isoaltion kit.

肿瘤代谢图谱（metabolic landscape）显著影响抗肿瘤免疫，但目前尚不清楚肿瘤起源器官中普遍激活的代谢通路如何调控免疫监视。本研究以肝脏为研究对象，发现一级结合胆汁酸与二级胆汁酸（bile acids, BAs）的蓄积是与肝细胞癌（hepatocellular carcinoma）及肝癌模型相关的代谢特征。通过在肝细胞中敲除BAAT以抑制结合型胆汁酸合成，可增强肿瘤特异性T细胞应答、抑制肿瘤生长，并使肿瘤对免疫检查点阻断治疗敏感。胆汁酸对CD8+ T细胞的调控具有差异性：一级胆汁酸如牛磺鹅去氧胆酸（taurochenodeoxycholic acid, TCDCA）可诱导氧化应激，而二级胆汁酸如石胆酸（lithocholic acid, LCA）则通过内质网应激（endoplasmic reticulum stress, ER stress）损伤T细胞功能，该效应可被熊去氧胆酸（ursodeoxycholic acid, UDCA）拮抗。事实上，通过膳食补充熊去氧胆酸可抑制肿瘤进展。本研究结果揭示了调控器官特异性代谢物如何影响抗肿瘤免疫，同时表明，干预胆汁酸合成或调整膳食摄入可增强肝癌的免疫治疗效果。实验整体设计：本研究旨在探究胆汁酸处理对T细胞基因表达的影响。通过对经不同胆汁酸处理的T细胞进行RNA测序（RNA-seq）获取数据，开展基因表达谱分析。将体外活化的CD8+ T细胞与不同胆汁酸共培养24小时，随后使用Qiagen RNA分离试剂盒提取RNA。