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: Mice, Knockout; 0301 basic medicine; Mice, Inbred BALB C; Epithelial-Mesenchymal Transition; Science; Q; 610; Membrane Proteins; Article; B7-H1 Antigen; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; DNA Topoisomerases, Type II; Hexosyltransferases; Cell Line, Tumor; Neoplasms; Neoplastic Stem Cells; Animals; Humans; Female; Poly-ADP-Ribose Binding Proteins; beta Catenin; Immune Evasion

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