| First Author | Wu M | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 3500 |
| PubMed ID | 34108491 | Mgi Jnum | J:307912 |
| Mgi Id | MGI:6725417 | Doi | 10.1038/s41467-021-23864-9 |
| Citation | Wu M, et al. (2021) WSX1 act as a tumor suppressor in hepatocellular carcinoma by downregulating neoplastic PD-L1 expression. Nat Commun 12(1):3500 |
| abstractText | 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-PI3Kdelta and thereby inactivates AKT, reducing AKT-induced GSK3beta inhibition. Activated GSK3beta 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 PI3Kdelta/AKT/GSK3beta/PD-L1 pathway. Our results may yield insights into the host homeostatic control of immune response and benefit the development of cancer immunotherapies. |
