2. Academic Validation
  3. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion

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

  • Nat Commun. 2018 May 15;9(1):1908. doi: 10.1038/s41467-018-04313-6.
Jung-Mao Hsu 1,  Weiya Xia 1,  Yi-Hsin Hsu 1,  Li-Chuan Chan 1 2,  Wen-Hsuan Yu 1 2,  Jong-Ho Cha 1 3,  Chun-Te Chen 1,  Hsin-Wei Liao 1 2 4,  Chu-Wei Kuo 5,  Kay-Hooi Khoo 5,  Jennifer L Hsu 1 6,  Chia-Wei Li 1,  Seung-Oe Lim 1,  Shih-Shin Chang 1 2,  Yi-Chun Chen 1,  Guo-Xin Ren 7,  Mien-Chie Hung 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 2 The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, 77030, USA.
  • 3 Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea.
  • 4 Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA, 02114, USA.
  • 5 Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan.
  • 6 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, 404, Taiwan.
  • 7 Department of Oral and Maxillofacial, Head and Neck Oncology, Affiliated 9th People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200011, China.
  • 8 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. mhung@mdanderson.org.
  • 9 The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, 77030, USA. mhung@mdanderson.org.
  • 10 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, 404, Taiwan. mhung@mdanderson.org.
  • 11 Department of Biotechnology, Asia University, Taichung, 413, Taiwan. mhung@mdanderson.org.
PMID: 29765039 DOI: 10.1038/s41467-018-04313-6
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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