Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression

Limo Chen, Don L. Gibbons, Sangeeta Goswami, Maria Angelica Cortez, Young Ho Ahn, Lauren A. Byers, Xuejun Zhang, Xiaohui Yi, David Dwyer, Wei Lin, Lixia Diao, Jing Wang, Jonathon D. Roybal, Mayuri Patel, Christin Ungewiss, David Peng, Scott Antonia, Melanie Mediavilla-Varela, Gordon Robertson, Steve JonesMilind Suraokar, James W. Welsh, Baruch Erez, Ignacio I. Wistuba, Lieping Chen, Di Peng, Shanshan Wang, Stephen E. Ullrich, John V. Heymach, Jonathan M. Kurie, F. Xiao Feng Qin

Research output: Contribution to journalArticlepeer-review

570 Scopus citations

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.

Original languageEnglish
Article number5241
JournalNature Communications
Volume5
DOIs
StatePublished - 28 Oct 2014

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