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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.
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1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA
3 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, Korea
4 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA; Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA, USA
5 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
6 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
7 Department of Oral and Maxillofacial, Head and Neck Oncology, Affiliated 9th People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
8 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan