Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Pediatrics, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Cancer Res. 2017 Aug 1;77(15):4065-4077. doi: 10.1158/0008-5472.CAN-17-0090. Epub 2017 Jun 16.
The intestine-specific homeobox transcription factor intestine-specific homeobox (ISX) is an IL6-inducible proto-oncogene implicated in the development of hepatocellular carcinoma, but its mechanistic contributions to this process are undefined. In this study, we provide evidence that ISX mediates a positive feedback loop integrating inflammation, tryptophan catabolism, and immune suppression. We found that ISX-mediated IL6-induced expression of the tryptophan catabolic enzymes Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase in hepatocellular carcinoma cells, resulting in an ISX-dependent increase in the tryptophan catabolite kynurenine and its receptor aryl hydrocarbon receptor (AHR). Activation of this kynurenine/AHR signaling axis acted through a positive feedback mechanism to increase ISX expression and enhance cellular proliferation and tumorigenic potential. RNAi-mediated attenuation of ISX or AHR reversed these effects. In an IDO1-dependent manner, ectopic expression of ISX induced expression of genes encoding the critical immune modulators CD86 (B7-2) and programmed death ligand-1 (PD-L1), through which ISX conferred a significant suppressive effect on the CD8 T-cell response. In hepatocellular carcinoma specimens, expression of IDO1, kynurenine, AHR, and PD-L1 correlated negatively with survival. Overall, our results identified a feed-forward mechanism of immune suppression in hepatocellular carcinoma organized by ISX, which involves kynurenine-AHR signaling and PD-L1, offering insights into immune escape by hepatocellular carcinoma, which may improve its therapeutic management. .
肠特异性同源盒转录因子肠特异性同源盒（ISX）是一种 IL6 诱导的原癌基因，与肝细胞癌的发展有关，但它在这一过程中的机制贡献尚不清楚。在这项研究中，我们提供的证据表明，ISX 介导了一个整合炎症、色氨酸分解代谢和免疫抑制的正反馈回路。我们发现，ISX 介导的 IL6 诱导的肝细胞癌细胞中色氨酸分解代谢酶吲哚胺 2,3-双加氧酶 1（IDO1）和色氨酸 2,3-双加氧酶的表达，导致色氨酸代谢物犬尿氨酸及其受体芳香烃受体（AHR）的 ISX 依赖性增加。这条犬尿氨酸/AHR 信号通路的激活通过正反馈机制作用，增加 ISX 的表达，增强细胞增殖和致瘤潜能。RNAi 介导的 ISX 或 AHR 衰减逆转了这些效应。以 IDO1 依赖的方式，ISX 的异位表达诱导了关键免疫调节剂 CD86（B7-2）和程序性死亡配体-1（PD-L1）的基因表达，通过这种方式，ISX 对 CD8 T 细胞反应产生了显著的抑制作用。在肝细胞癌标本中，IDO1、犬尿氨酸、AHR 和 PD-L1 的表达与存活率呈负相关。总的来说，我们的研究结果确定了由 ISX 组织的肝细胞癌免疫抑制的前馈机制，该机制涉及犬尿氨酸-AHR 信号和 PD-L1，为肝细胞癌的免疫逃避提供了深入了解，这可能会改善其治疗管理。
