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Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Nat+Commun 2018 ; 9 (ä): ä Nephropedia Template TP
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STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion #MMPMID29765039
Hsu JM; Xia W; Hsu YH; Chan LC; Yu WH; Cha JH; Chen CT; Liao HW; Kuo CW; Khoo KH; Hsu JL; Li CW; Lim SO; Chang SS; Chen YC; Ren Gx; Hung MC
Nat Commun 2018[]; 9 (ä): ä PMID29765039show ga
Enriched 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/?-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through ?-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/?-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear ?-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.