Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression

作者：Zhang, Heng; Chen, Gang; Feng, Xing; Song, Huiwen; Meng, Lingbing; Fu, Yao; Yang, Jun; Fan, Zhiwen; Ding, Youxiang; Du, Zhijie; Wang, Jianchao; Yang, Li; Zhang, Jun; Sun, Lixia; Liu, Zhigang; Zhang, Zhiyong^*; Li, Quanhai^*; Fan, Xiangshan^*

来源：EMBO Molecular Medicine, 2023, 15(5).

DOI：10.15252/emmm.202215924

• MDSC
• PD-1
• TNF alpha
• UVRAG
• WDR6

The WD-repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1-6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune-competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A-DDB1-ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFa locus by blocking autophagic degradation of p65, elevates intratumoral myeloid-derived suppressor cell (MDSC) number, and reduces CD8(+) T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFa blockade. TNFa recruits NF-?B to activate the transcription of WDR6, establishing a WDR6-TNFa loop. Clinically, the WDR6/UVRAG/NF-?B pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR-like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti-PD-L1 against HCC with WDR6 dysregulation.

• 单位
  河北医科大学; 1; 上海大学; 中国医学科学院; 武汉大学