Intestine-Specific Homeobox Gene ISX Integrates IL6 Signaling, Tryptophan Catabolism, and Immune Suppression.

Abstract

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. Cancer Res; 77(15); 4065-77. ©2017 AACR.

• Authors: Li-Ting Wang, Shyh-Shin Chiou, Chee-Yin Chai, Edward Hsi, Kazunari K Yokoyama, Shen-Nien Wang, Shau-Ku Huang, Shih-Hsien Hsu
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 15 Pg. 4065-4077 (08 01 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28625979 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Homeodomain Proteins
• IL6 protein, human
• Interleukin-6
• Isx protein, human
• MAS1 protein, human
• Proto-Oncogene Mas
• Transcription Factors
• Tryptophan

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Blotting, Western
• Carcinoma, Hepatocellular (immunology, metabolism)
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Female
• Gene Expression Regulation, Neoplastic (physiology)
• Homeodomain Proteins (metabolism)
• Humans
• Immunohistochemistry
• Interleukin-6 (metabolism)
• Liver Neoplasms (immunology, metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Proto-Oncogene Mas
• Real-Time Polymerase Chain Reaction
• Signal Transduction (physiology)
• Transcription Factors (metabolism)
• Tryptophan (metabolism)
• Tumor Escape (physiology)