@article{84467e4e68ce4b8ebe8f2622ed20d7c1,
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.",
author = "Limo Chen and Gibbons, {Don L.} and Sangeeta Goswami and Cortez, {Maria Angelica} and Ahn, {Young Ho} and Byers, {Lauren A.} and Xuejun Zhang and Xiaohui Yi and David Dwyer and Wei Lin and Lixia Diao and Jing Wang and Roybal, {Jonathon D.} and Mayuri Patel and Christin Ungewiss and David Peng and Scott Antonia and Melanie Mediavilla-Varela and Gordon Robertson and Steve Jones and Milind Suraokar and Welsh, {James W.} and Baruch Erez and Wistuba, {Ignacio I.} and Lieping Chen and Di Peng and Shanshan Wang and Ullrich, {Stephen E.} and Heymach, {John V.} and Kurie, {Jonathan M.} and Qin, {F. Xiao Feng}",
note = "Funding Information: We thank Dr Ying Ma, Nasser Kazimi and Jessica Cabrejos for expert advice and technical assistance. This work was supported by ACS RSG LIB-117155, 5-P50-CA70907-12 PP-3b, NSFC Grant (no. 31170832) and Guangdong Innovation Research Team Program (no. 201001Y0104687244), MOST PPG (2014CB745203) and RSFPWIH Grant (201302018) to F.X.-F.Q.; 5-R01-CA132608-03, 5-P50-CA70907-12 PP-3 to J.M.K. and J.V.H.; 5-R01-CA168484-04 (J.V.H.); ACS RSG-10-056-01-LIB (S.E.U.); NIH Cancer Center Support Grant (CA016672) to MDACC core facilities; Rexanna{\textquoteright}s Foundation for Fighting Lung Cancer, The Stading Lung Cancer Research Fund, MD Anderson Cancer Center Physician Scientist Award and K08-CA151651 to D.L.G.; MD Anderson Cancer Center Physician Scientist Award, Sidney Kimmel Scholar Award and the Cancer Clinical Investigator Team Leadership Award (P30CA016672) to L.A.B.; Training Program in Molecular Genetics of Cancer, NCI T32 CA009299-32 (C.U.). D.L.G. and L.A.B. are R. Lee Clark Fellows of the University of Texas MD Anderson Cancer Center, supported by the Jeane F. Shelby Scholarship Fund. CPRIT Training Grant (RP140106) to D.P. The study was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program. We would like to thank the members of our labs and Dr James Allison and Dr Padmanee Sharma for critical reading of the manuscript. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",
year = "2014",
month = oct,
day = "28",
doi = "10.1038/ncomms6241",
language = "English",
volume = "5",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}