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

• Published in: Nature communications Vol. 9; no. 1; pp. 1908 - 17
• Main Authors: Hsu, Jung-Mao, Xia, Weiya, Hsu, Yi-Hsin, Chan, Li-Chuan, Yu, Wen-Hsuan, Cha, Jong-Ho, Chen, Chun-Te, Liao, Hsin-Wei, Kuo, Chu-Wei, Khoo, Kay-Hooi, Hsu, Jennifer L., Li, Chia-Wei, Lim, Seung-Oe, Chang, Shih-Shin, Chen, Yi-Chun, Ren, Guo-xin, Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 14/19; 631/67; 631/80/458/1524; 82/29; 96/106; 96/35; Animals; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; beta Catenin - genetics; beta Catenin - immunology; Cancer; Cancer immunotherapy; Cell Line, Tumor; DNA Topoisomerases, Type II - genetics; DNA Topoisomerases, Type II - immunology; Enrichment; Epithelial-Mesenchymal Transition; Etoposide; Female; Gene Expression Regulation, Neoplastic; Glycosylation; Glycosyltransferase; Hexosyltransferases - genetics; Hexosyltransferases - immunology; Humanities and Social Sciences; Humans; Immune Evasion; Immunotherapy; Membrane Proteins - genetics; Membrane Proteins - immunology; Mesenchyme; Mice, Inbred BALB C; Mice, Knockout; multidisciplinary; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - physiopathology; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - immunology; PD-L1 protein; Poly-ADP-Ribose Binding Proteins - genetics; Poly-ADP-Ribose Binding Proteins - immunology; Science; Science (multidisciplinary); Stem cells; Transcription; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04313-6

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/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. PD-L1 accumulates on cancer stem cells and favours immune evasion but the mechanism underlying this accumulation are unknown. Here the authors show that epithelial-mesenchymal transition induces glycosylation and stabilisation of PD-L1; antagonising this process renders cancer cells sensitive to anti-Tim3-therapy.