The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200.

The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200.

Oncoimmunology. 2017;6(1):e1263412

Authors: Noman MZ, Janji B, Abdou A, Hasmim M, Terry S, Tan TZ, Mami-Chouaib F, Thiery JP, Chouaib S

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 antibody-mediated 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.

PMID: 28197390 [PubMed - in process]

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