WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and ranks as the fifth leading cause of cancer-related mortality. The development of HCC is a multifactorial process in which genetic and epigenetic alterations in regulatory genes result in the activation of oncogenes and inactivation of tumor suppressor genes. However, so far, the mechanism by which HCC cells induce immunotolerance and escape from host homeostatic immunosurveillance remains unclear.

Programmed death ligand-1 (PD-L1) is a critical immune checkpoint protein whose engagement with its receptor, programmed death 1 (PD-1), on T cells activates co-inhibitory signaling to suppress effector T-cell function. The physiological role of the PD-L1/PD-1 axis is maintaining the balance between peripheral tolerance and autoimmunity, but cancer cells hijack this process to escape from host immune surveillance.

Nonetheless, little is known about the mechanism underlying the homeostatic control of PD-L1 expression and its dysregulation in cancer. Understanding the multifaceted control of PD-L1 would facilitate the development of more effective therapeutic strategies.

WSX1, a receptor subunit for IL-27, is widely expressed in immune cells and closely involved in immune response, but its function in nonimmune cells remains unknown. 

WSX1, homologous to the IL-12 receptor β2 chain, is a class I cytokine receptor, which consists of a single transmembrane domain, a WSX1 signature motif, a box 1 motif in its intracellular region, and 7 potential N-glycosylation sites in its extracellular domain. WSX1, together with gp130, constitutes a functional signal-transducing receptor for IL-27; lack of either subunit attenuates IL-27-mediated signaling. WSX1 was previously thought to be expressed exclusively in immune cells, mediating IL-27-dependent pro-inflammatory or anti-inflammatory immune responses. However, we and others previously demonstrated that WSX1 is also expressed in multiple types of epithelial tumor cells, including breast tumors, melanomas, and lung carcinomas. The presence of WSX1 sensitized IL-27-independent natural killer (NK) cell-mediated antitumor surveillance in breast tumors and inhibited melanoma growth in an IL-27-dependent manner. In addition, a recent study reported that WSX1 deficiency in mice promoted the oncogenic properties of mutant p53, indicating a tumor-suppressive role of WSX1. These published biological functions of WSX1 largely depend on the presence of its ligand IL-27.

Scientists from the University of Texas MD Anderson Cancer Center reveal an IL-27-independent biological function of WSX1 as a potential HCC suppressor, a function that relies primarily on WSX1’s regulation of CD8+ T cell-mediated adaptive immunity. In brief, they use multiple human tissue microarrays, spontaneous HCC mouse models, and current immune and molecular profiling tools to show that WSX1 downregulates neoplastic PD-L1 and reduces CD8+ T-cell exhaustion in the tumor microenvironment, leading to inhibition of oncogene-mediated HCC formation.

They found that WSX1 is highly expressed in human normal liver tissues, and its downregulation in HCC closely correlated with poor prognosis.WSX1 retards HCC development in vivo independently of IL-27. WSX1 impedes HCC development by maximizing CD8+ T cell-mediated antitumor immunosurveillance. WSX1 relieves PD-L1/PD-1 axis-induced T-cell exhaustion by downregulating PD-L1 expression in tumor cells. WSX1 destabilizes PD-L1 by enhancing GSK3β-mediated PD-L1 protein degradation. WSX1 enhances GSK3β activity by inactivating the PI3Kδ/AKT signaling pathway.

In summary, on the basis of the above results, they are able to reveal an interaction model of WSX1, PI3Kδ, AKT, GSK3β, and PD-L1. Specifically, in physiological conditions, WSX1 is highly expressed in hepatocytes and contributes to the tight control of PD-L1 levels through governing the PI3Kδ/AKT/GSK3β signaling pathway, ensuring a homeostatic PD-L1 expression level on normal hepatocytes, and thereby enabling effective CD8+ T-cell-mediated immunosurveillance. However, when WSX1 is downregulated by multiple oncogenic signals, PI3Kδ escapes from WSX1-mediated transcriptional inactivation, resulting in the subsequent activation of AKT. Hyperactive AKT then inactivates GSK3β and thereby blocks GSK3β-mediated PD-L1 degradation, which results in excessive PD-L1 expression on malignant hepatocytes, leading to PD-L1/PD-1 axis-mediated tumor immune evasion and, ultimately, HCC development. Their research has been published in Nature Communications.

 

Sherry