LAUSR

Introduction The intestine-specific homeobox transcription factor intestine specific homeobox (ISX) is an IL6-inducible protooncogene implicated in the development of hepatocellular carcinoma, but its mechanistic contributions to this process are undefined. Material and methods In this study, we provide evidence that ISX mediates a positive feedback loop integrating inflammation, tryptophan catabolism,and immune suppression. Results and discussions We found that ISX-mediated IL6-induced expression of the tryptophan catabolic enzymes Indoleamine2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenasein 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. Conclusion 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