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

• Published in: Nature communications Vol. 12; no. 1; pp. 3500 - 16
• Main Authors: Wu, Man, Xia, Xueqing, Hu, Jiemiao, Fowlkes, Natalie Wall, Li, Shulin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/106; 13/109; 13/31; 13/44; 13/51; 13/89; 13/95; 14/63; 38; 49/88; 49/91; 631/67/1504/1610/4029; 631/67/580; 64/110; 64/60; 692/4028/67/1504/1610; 82/29; 82/58; 82/80; AKT protein; Animal models; Antitumor activity; Cancer; Cancer immunotherapy; CD8 antigen; Hepatocellular carcinoma; Hepatocytes; Humanities and Social Sciences; Immune response; Immune system; Immunosurveillance; Interleukin 27; Liver cancer; Lymphocytes; Lymphocytes T; multidisciplinary; PD-L1 protein; Receptors; Science; Science (multidisciplinary); Transcription; Tumor suppressor genes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23864-9

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. Here we report that WSX1 is highly expressed in human hepatocytes but downregulated in hepatocellular carcinoma (HCC) cells. Using NRAS/AKT -derived spontaneous HCC mouse models, we reveal an IL-27–independent tumor-suppressive effect of WSX1 that largely relies on CD8 + T-cell immune surveillance via reducing neoplastic PD-L1 expression and the associated CD8 + T-cell exhaustion. Mechanistically, WSX1 transcriptionally downregulates an isoform of PI3K—PI3Kδ and thereby inactivates AKT, reducing AKT-induced GSK3β inhibition. Activated GSK3β then boosts PD-L1 degradation, resulting in PD-L1 reduction. Overall, we demonstrate that WSX1 is a tumor suppressor that reinforces hepatic immune surveillance by blocking the PI3Kδ/AKT/GSK3β/PD-L1 pathway. Our results may yield insights into the host homeostatic control of immune response and benefit the development of cancer immunotherapies. The biological functions of WSX1, the alpha subunit of the interleukin-27 receptor, in non-immune cells are largely unknown. Here, the authors propose an IL-27-independent tumor suppressor role for WSX1 in hepatocytes, showing that WSX1 restricts tumor progression by down-regulating PD-L1 expression in tumour cells and maximizing T cell mediated antitumor immune responses.