title: Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression.
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.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Limo
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Goswami
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Maria Angelica
authors.initials: MA
authors.lastname: Cortez
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Molecular Medicine, Ewha Womans University School of Medicine, 1071 Anyangcheonro, Yangcheon-gu, Seoul 158-710, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Byers
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yi
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dwyer
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.affiliation: Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Roybal
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mayuri
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Christin
authors.initials: C
authors.lastname: Ungewiss
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL33612, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Antonia
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL33612, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Mediavilla-Varela
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Robertson
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Milind
authors.initials: M
authors.lastname: Suraokar
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Welsh
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Baruch
authors.initials: B
authors.lastname: Erez
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Immunobiology, Yale School of Medicine, 10 Amistad Street, New Haven, CT 06519, USA.
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, Sun Yat-Sen University, Guangzhou, 510275, China.
authors.forename: Di
authors.initials: D
authors.lastname: Peng
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, Sun Yat-Sen University, Guangzhou, 510275, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Ullrich
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, Sun Yat-Sen University, Guangzhou, 510275, China.
authors.forename: F Xiao-Feng
authors.initials: FX
authors.lastname: Qin
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019992:Databases as Topic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D018390:Gene Targeting; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D007109:Immunity; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010641:Phenotype; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D014157:Transcription Factors; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1