The tumor microenvironment (TME) influences cancer growth, proliferation, and response to therapy. Varanasi et al. investigated whether organ-specific metabolites in the TME affect tumor progression and antitumor immune responses in liver cancer (see the Perspective by Goessling). Bile acids are produced in the liver and are required for the digestion and absorption of lipids. Analysis of the enzymes involved in bile acid synthesis revealed elevated levels of the bile acid–conjugating enzyme BAAT (bile acid-CoA:amino acid N-acyltransferase) in patients with hepatocellular carcinoma. Using experimental models of liver cancer, deletion of BAAT improved the antitumor immune responses. Primary bile acids could accumulate in T cells and induce DNA damage, whereas certain secondary bile acids impaired T cell function. Dietary supplementation with ursodeoxycholic acid (ursodiol) boosted T cell function and enhanced immunosurveillance. —Priscilla N. Kelly
The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid–CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.
肿瘤微环境（TME）影响癌症的生长、增殖和对治疗的反应。Varanasi等人研究了TME中器官特异性代谢物是否影响肝癌的肿瘤进展和抗肿瘤免疫反应（参见Goessling的Perspective）。胆汁酸在肝脏中产生，是消化和吸收脂质所必需的。对参与胆汁酸合成的酶的分析显示，肝细胞癌患者中胆汁酸结合酶BAAT（胆汁酸-CoA:氨基酸N-酰基转移酶）的水平升高。使用肝癌的实验模型，删除BAAT改善了抗肿瘤免疫反应。初级胆汁酸可以在T细胞中积累并诱导DNA损伤，而某些次级胆汁酸损害T细胞功能。膳食补充熊去氧胆酸（ursodiol）增强了T细胞功能并加强了免疫监视。—Priscilla N. Kelly
癌症的代谢景观极大地影响抗肿瘤免疫，但肿瘤微环境中器官特异性代谢物如何影响免疫监视仍不清楚。我们发现，初级结合胆汁酸和次级胆汁酸（BAs）的积累是人类肝细胞癌和实验性肝癌模型的代谢特征。通过删除胆汁酸结合酶胆汁酸-CoA:氨基酸N-酰基转移酶（BAAT）来抑制肝细胞中结合BA的合成，增强了肿瘤特异性T细胞反应，减少了肿瘤生长，并使肿瘤对抗程序性细胞死亡蛋白1（抗PD-1）免疫治疗敏感。此外，不同的BAs以不同方式调节CD8+ T细胞；初级BAs诱导氧化应激，而次级胆汁酸石胆酸通过内质网应激抑制T细胞功能，这被熊去氧胆酸抵消。我们证明，修改BA合成或膳食摄入熊去氧胆酸可以改善肝癌模型系统中的肿瘤免疫治疗。
Bile acid synthesis impedes tumor-specific T cell responses during liver cancer
肿瘤(癌症)患者之家