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

Nature Communications
Jung-Mao HsuMien-Chie Hung

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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Citations

Mar 16, 2019·Stem Cells·Mathieu J F CrupiRagunath Singaravelu
Jul 16, 2019·The Journal of Clinical Investigation·Li-Chuan ChanMien-Chie Hung
Jan 18, 2020·Journal of Clinical Medicine·Cinzia FiondaAngela Santoni
May 23, 2020·Journal for Immunotherapy of Cancer·Kellsye P FabianJames W Hodge
May 30, 2020·Cell Research·Xing He, Chenqi Xu
Oct 17, 2019·Cold Spring Harbor Perspectives in Medicine·Jong-Ho ChaMien-Chie Hung
Feb 8, 2019·Science Translational Medicine·Alessandro Prestipino, Robert Zeiser
May 8, 2020·Journal of Oncology·Shu-Man LiDan Xie
Sep 7, 2020·Journal of Experimental & Clinical Cancer Research : CR·Hao ZhangChengyi Sun
Jun 14, 2019·Oxidative Medicine and Cellular Longevity·Yongli LiChangzheng Li
May 12, 2020·Frontiers in Molecular Biosciences·Deguang KongHeide L Ford
Apr 22, 2020·Oncoimmunology·Fatmah A MansourHazem Ghebeh
Jul 6, 2020·Journal of Biomedical Science·Ying-Nai WangMien-Chie Hung
Mar 6, 2019·Frontiers in Cell and Developmental Biology·Alice TurdoGiorgio Stassi
Mar 8, 2019·Cancers·Narayanasamy Badrinath, So Young Yoo
Apr 25, 2020·World Journal of Gastroenterology : WJG·Mihaela Chivu-EconomescuCarmen Cristina Diaconu
Jul 2, 2019·Frontiers in Immunology·Xiangfeng ShenZhi-Xiang Xu
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Jan 11, 2020·Frontiers in Immunology·Elena Martin-OrozcoMaria Ayala-San Nicolas
Nov 8, 2020·Cell Death & Disease·Qian GouYongzhong Hou
Dec 3, 2020·International Journal of Molecular Sciences·Lorenzo CastagnoliSerenella M Pupa

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Methods Mentioned

BETA
glycosylation
transfection
ChIP-seq
biopsy
immunoprecipitation
flow cytometry
proximity ligation
PCR
deamidation

Software Mentioned

AxioVision
Cluster
Excel
FlowJo
GraphPad Prism
ImageJ

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