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

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 and Mien-Chie Hung ()
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Jung-Mao Hsu: The University of Texas MD Anderson Cancer Center
Weiya Xia: The University of Texas MD Anderson Cancer Center
Yi-Hsin Hsu: The University of Texas MD Anderson Cancer Center
Li-Chuan Chan: The University of Texas MD Anderson Cancer Center
Wen-Hsuan Yu: The University of Texas MD Anderson Cancer Center
Jong-Ho Cha: The University of Texas MD Anderson Cancer Center
Chun-Te Chen: The University of Texas MD Anderson Cancer Center
Hsin-Wei Liao: The University of Texas MD Anderson Cancer Center
Chu-Wei Kuo: Academia Sinica
Kay-Hooi Khoo: Academia Sinica
Jennifer L. Hsu: The University of Texas MD Anderson Cancer Center
Chia-Wei Li: The University of Texas MD Anderson Cancer Center
Seung-Oe Lim: The University of Texas MD Anderson Cancer Center
Shih-Shin Chang: The University of Texas MD Anderson Cancer Center
Yi-Chun Chen: The University of Texas MD Anderson Cancer Center
Guo-xin Ren: Shanghai Jiaotong University
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04313-6

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