CD47 is a direct target of SNAI1 and ZEB1 and its blockade activates the phagocytosis of breast cancer cells undergoing EMT

Muhammad Zaeem Noman, Kris Van Moer, Vanessa Marani, Robert M. Gemmill, Léon Charles Tranchevent, Francisco Azuaje, Arnaud Muller, Salem Chouaib, Jean Paul Thiery, Guy Berchem, Bassam Janji*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

45 Citations (Scopus)

Abstract

We report that CD47 was upregulated in different EMT-activated human breast cancer cells versus epithelial MCF7 cells. Overexpression of SNAI1 or ZEB1 in epithelial MCF7 cells activated EMT and upregulated CD47 while siRNA-mediated targeting of SNAI1 or ZEB1 in mesenchymal MDA-MB-231 cells reversed EMT and strongly decreased CD47. Mechanistically, SNAI1 and ZEB1 upregulated CD47 by binding directly to E-boxes in the human CD47 promoter. TCGA and METABRIC data sets from breast cancer patients revealed that CD47 correlated with SNAI1 and Vimentin. At functional level, different EMT-activated breast cancer cells were less efficiently phagocytosed by macrophages vs. MCF7 cells. The phagocytosis of EMT-activated cells was rescued by using CD47 blocking antibody or by genetic targeting of SNAI1, ZEB1 or CD47. These results provide a rationale for an innovative preclinical combination immunotherapy based on PD-1/PD-L1 and CD47 blockade along with EMT inhibitors in patients with highly aggressive, mesenchymal, and metastatic breast cancer.

Original languageEnglish
Article numbere1345415
JournalOncoImmunology
Volume7
Issue number4
DOIs
Publication statusPublished - 3 Apr 2018

Keywords

  • Breast cancer
  • CD47
  • Dendritic cells
  • Epithelial to Mesenchymal Transition
  • Immune checkpoint
  • Macrophage
  • Phagocytosis and Immunotherapy
  • ZEB1

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