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
  • 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. [email protected].
  • 9. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, 77030, USA. [email protected].
  • 10. Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, 404, Taiwan. [email protected].
  • 11. Department of Biotechnology, Asia University, Taichung, 413, Taiwan. [email protected].
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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