期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-04313-6
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资金
- National Institutes of Health [CCSG CA016672]
- Cancer Prevention & Research Institutes of Texas [DP150052, RP160710]
- National Breast Cancer Foundation, Inc.
- Breast Cancer Research Foundation
- Patel Memorial Breast Cancer Endowment Fund
- University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund
- Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE) [MOST 105-2911-I-002-302]
- Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence [MOHW106-TDU-B-212-144003]
- Center for Biological Pathways
- National Research Foundation of Korea grant for the Global Core Research Center - the Korea government (MSIP) [2011-0030001]
- NATIONAL CANCER INSTITUTE [P30CA016672] Funding Source: NIH RePORTER
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/ss-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through beta-catenin, and subsequent STT3-dependent PD-L1 Nglycosylation 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/beta-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear beta-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.
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