STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion

• DOI: 10.1038/s41467-018-04313-6
• Publication Date: 2018-05-09T09:53:13Z
• Authors: Jung-Mao Hsu; Weiya Xia; Yi-Hsin Hsu; Li-Chuan Chan; Wen-Hsuan Yu; Jong-Ho Cha; Chun-Te Chen; Hsin-Wei Liao; Chu-Wei Kuo; Kay-Hooi Khoo; Jennifer L. Hsu; Chia-Wei Li; Seung-Oe Lim; Shih-Shin Chang; Yi-Chun Chen; Guo-xin Ren; Mien-Chie Hung
• Keywords: Cancer Immunotherapy

Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying enrichment CSCs remain unclear. Here, we demonstrate that epithelial-mesenchymal transition (EMT) enriches by EMT/β-catenin/STT3/PD-L1 signaling axis, which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent N-glycosylation stabilizes upregulates PD-L1. The axis is also utilized general cell population, but it has much more profound effect on as than non-CSCs. We further identify a non-canonical mesenchymal-epithelial (MET) activity of etoposide, suppresses TOP2B degradation-dependent nuclear β-catenin reduction, leading downregulation non-CSCs sensitization anti-Tim-3 therapy. Together, our results link MET stabilization glycosylation regulation reveal potential strategy enhance immunotherapy efficacy.