The immune checkpoint ligand PD-l1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200

Muhammad Zaeem Noman, Bassam Janji, Abderemane Abdou, Meriem Hasmim, Stéphane Terry, Tuan Zea Tan, Fathia Mami-Chouaib, Jean Paul Thiery, Salem Chouaib*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

157 Citations (Scopus)

Abstract

PD-L1 expression and regulation by mesenchymal tumor cells remain largely undefined. Here, we report that among different EMT-activated MCF7 human breast cancer cell clones, PD-L1 was differentially upregulated in MCF7 sh-WISP2, MCF7–1001/2101, and MDA-MB-231 cells but not in MCF7 SNAI1 and MCF7 SNAI1–6SA cells. Mechanistic investigations revealed that siRNA silencing of ZEB-1, but not SNAI1, TWIST, or SLUG and overexpression of miR200 family members in MCF7 sh-WISP2 cells strongly decreased PD-L1 expression. Thus, we propose that PD-L1 expression in EMT-activated breast cancer cells depends on the EMT-TF involved in EMT activation. Interestingly, siRNA-mediated targeting of PD-L1 or antibodymediated PD-L1 block restored the susceptibility of highly resistant MCF7 sh-WISP2 and MCF7–2101 cells to CTL-mediated killing. Additionally, these results provide a novel preclinical rationale to explore EMT inhibitors as adjuvants to boost immunotherapeutic responses in subgroups of patients in whom malignant progression is driven by different EMT-TFs.

Original languageEnglish
Article numbere1263412
JournalOncoImmunology
Volume6
Issue number1
DOIs
Publication statusPublished - 2 Jan 2017

Keywords

  • Breast cancer
  • Epithelial-tomesenchymal transition
  • MiR-200 and immunotherapy
  • PD-L1
  • SLUG (SNAI2)
  • SNAI1
  • ZEB-1

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