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 Jones, Milind Suraokar, James W. Welsh, Baruch Erez, Ignacio I. Wistuba, Lieping Chen, Di Peng, Shanshan Wang, Stephen E. Ullrich, John V. Heymach (), Jonathan M. Kurie () and F. Xiao-Feng Qin ()
Additional contact information
Limo Chen: The University of Texas MD Anderson Cancer Center
Don L. Gibbons: The University of Texas MD Anderson Cancer Center
Sangeeta Goswami: The University of Texas MD Anderson Cancer Center
Maria Angelica Cortez: The University of Texas MD Anderson Cancer Center
Young-Ho Ahn: The University of Texas MD Anderson Cancer Center
Lauren A. Byers: The University of Texas MD Anderson Cancer Center
Xuejun Zhang: The University of Texas MD Anderson Cancer Center
Xiaohui Yi: The University of Texas MD Anderson Cancer Center
David Dwyer: The University of Texas MD Anderson Cancer Center
Wei Lin: The University of Texas MD Anderson Cancer Center
Lixia Diao: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Jonathon D. Roybal: The University of Texas MD Anderson Cancer Center
Mayuri Patel: The University of Texas MD Anderson Cancer Center
Christin Ungewiss: The University of Texas MD Anderson Cancer Center
David Peng: The University of Texas MD Anderson Cancer Center
Scott Antonia: H. Lee Moffitt Cancer Center
Melanie Mediavilla-Varela: H. Lee Moffitt Cancer Center
Gordon Robertson: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Steve Jones: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Milind Suraokar: The University of Texas MD Anderson Cancer Center
James W. Welsh: The University of Texas MD Anderson Cancer Center
Baruch Erez: The University of Texas MD Anderson Cancer Center
Ignacio I. Wistuba: The University of Texas MD Anderson Cancer Center
Lieping Chen: Yale School of Medicine
Di Peng: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, Sun Yat-Sen University
Shanshan Wang: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, Sun Yat-Sen University
Stephen E. Ullrich: The University of Texas MD Anderson Cancer Center
John V. Heymach: The University of Texas MD Anderson Cancer Center
Jonathan M. Kurie: The University of Texas MD Anderson Cancer Center
F. Xiao-Feng Qin: The University of Texas MD Anderson Cancer Center

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6241

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