title: The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200.
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.
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France; Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health (L.I.H), Luxembourg City, Luxembourg.
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health (L.I.H) , Luxembourg City, Luxembourg.
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, Université Paris-Saclay , Villejuif, France.
authors.forename: Abderemane
authors.initials: A
authors.lastname: Abdou
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, Université Paris-Saclay , Villejuif, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Hasmim
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, Université Paris-Saclay , Villejuif, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Terry
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore , Singapore.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, Université Paris-Saclay , Villejuif, France.
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; CNRS UMR 7057 Matter and Complex Systems, University Paris Denis Diderot, Paris, France.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, Université Paris-Saclay , Villejuif, France.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
keywords: Breast cancer; PD-L1; SLUG (SNAI2); SNAI1; ZEB-1; epithelial-to-mesenchymal transition; miR-200 and immunotherapy