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. .

MicroRNA-153 Decreases Tryptophan Catabolism and Inhibits Angiogenesis in Bladder Cancer by Targeting Indoleamine 2,3-Dioxygenase 1

“…Vacher et al reported that IDO1 induced secretion of IL1B, IL6, IL8, and CXCR4 in breast cancer (38). IL6 expression also promoted tryptophan metabolism to constitute a positive feedback loop (39). In the current study, we found that miR-153 expression reduced IL6 secretion in bladder cancer cells, thereby inhibiting STAT3 signaling and VEGF expression.…”

Targeting the IDO1 pathway in cancer: from bench to bedside

“…Importantly, several immune checkpoints (e.g., PD-1 and CTLA4) on the T cell surface modulate IDO1 expression in antigen-presenting cells. Recently, Wang et al [ 30 ] demonstrated that the IL-6-inducible proto-oncogene protein intestine-specific homeobox (ISX) gene induces IDO1 and TDO expression, which increases Kyn and AhR and thereby promotes the tumorigenic potential and immunosuppression of hepatocellular carcinoma cells expressing CD86 and PD-L1. Others report that hypoxia enhances IDO1 production in monocyte-derived dendritic cells, yet the underlying mechanisms remain elusive [ 31 ].…”

Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma

“…Our previous studies found that AHR promotes tumorigenesis by cooperating with a newly identified proto-oncogene, intestine-specific homeobox (ISX) in HCC [ 15 , 16 ]. Ablation of AHR or ISX in hepatoma cells suppresses cell growth, whereas its overexpression promotes cell proliferation and leads to enhanced in vitro and in vivo tumorigenic activity.…”

“…Tumor cells express programmed cell-death 1 ligand (PD-L1) and the cluster of differentiation 86 (CD86) protein binds to immune-checkpoint receptors programmed cell-death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) of CD8+ T-cell to inhibit host immune responses [ 17 ]. Our previous studies showed that liver tumors result in immune suppression by expressing PD-L1 and CD86 through induction by the AHR-ISX cascade [ 16 ]. The depletion of AHR or ISX in liver tumors converts the immune activity of CD8+ T-cells and promotes the death of liver tumor cells.…”