Intestine-specific homeobox gene ISX integrates IL6 signaling, tryptophan catabolism, and immune suppression

Li Ting Wang, Shyh Shin Chiou, Chee Yin Chai, Edward Hsi, Kazunari K. Yokoyama, Shen Nien Wang, Shau Ku Huang, Shih Hsien Hsu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)


The intestine-specific homeobox transcription factor intestinespecific 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 ISXdependent 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.

Original languageEnglish
Pages (from-to)4065-4077
Number of pages13
JournalCancer Research
Issue number15
Publication statusPublished - 2017 Aug 1
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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