Nature communications, 2018-05, Vol.9 (1), p.1908-17, Article 1908
2018
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion
- Ist Teil von
- Nature communications, 2018-05, Vol.9 (1), p.1908-17, Article 1908
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-018-04313-6Titel-ID: cdi_doaj_primary_oai_doaj_org_article_b6e5e0697fa048aeb6392035c75e7d85
- Format
- –
- Schlagworte
- 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, Humans, Immune Evasion, Immunotherapy, Membrane Proteins - genetics, Membrane Proteins - immunology, Mesenchyme, Mice, Inbred BALB C, Mice, Knockout, 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, Stem cells, Transcription, β-Catenin