Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression

Nat Commun. 2014 Oct 28;5:5241. doi: 10.1038/ncomms6241.

Abstract

Immunosuppression of tumour-infiltrating lymphocytes (TIL) is a common feature of advanced cancer, but its biological basis has remained obscure. We demonstrate here a molecular link between epithelial-to-mesenchymal transition (EMT) and CD8(+) TIL immunosuppression, two key drivers of cancer progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumour cells, leading to CD8(+) T-cell immunosuppression and metastasis. These findings are supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets. In addition to revealing a link between EMT and T-cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / metabolism*
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Databases as Topic
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Targeting
  • Homeodomain Proteins / metabolism*
  • Humans
  • Immune Tolerance*
  • Immunity
  • Kruppel-Like Transcription Factors / metabolism*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Biological
  • Neoplasm Metastasis
  • Phenotype
  • Transcription Factors / metabolism*
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • MIRN200 microRNA, human
  • MicroRNAs
  • Mirn200 microRNA, mouse
  • Transcription Factors
  • ZEB1 protein, human
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1