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; F. Xiao Feng Qin

doi:10.1038/ncomms6241

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 journal › Article › peer-review

468 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 language	English (US)
Article number	5241
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6241
State	Published - Oct 28 2014
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Chemistry
General Physics and Astronomy

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Chen, L., Gibbons, D. L., Goswami, S., Cortez, M. A., Ahn, Y. H., Byers, L. A., Zhang, X., Yi, X., Dwyer, D., Lin, W., Diao, L., Wang, J., Roybal, J. D., Patel, M., Ungewiss, C., Peng, D., Antonia, S., Mediavilla-Varela, M., Robertson, G., ... Qin, F. X. F. (2014). Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nature Communications, 5, Article 5241. https://doi.org/10.1038/ncomms6241

Chen, L, Gibbons, DL, Goswami, S, Cortez, MA, Ahn, YH, Byers, LA, Zhang, X, Yi, X, Dwyer, D, Lin, W, Diao, L, Wang, J, Roybal, JD, Patel, M, Ungewiss, C, Peng, D, Antonia, S, Mediavilla-Varela, M, Robertson, G, Jones, S, Suraokar, M, Welsh, JW, Erez, B, Wistuba, II, Chen, L, Peng, D, Wang, S, Ullrich, SE, Heymach, JV, Kurie, JM & Qin, FXF 2014, 'Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression', Nature Communications, vol. 5, 5241. https://doi.org/10.1038/ncomms6241

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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}",

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doi = "10.1038/ncomms6241",

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AU - Chen, Limo

AU - Gibbons, Don L.

AU - Goswami, Sangeeta

AU - Cortez, Maria Angelica

AU - Ahn, Young Ho

AU - Byers, Lauren A.

AU - Zhang, Xuejun

AU - Yi, Xiaohui

AU - Dwyer, David

AU - Lin, Wei

AU - Diao, Lixia

AU - Wang, Jing

AU - Roybal, Jonathon D.

AU - Patel, Mayuri

AU - Ungewiss, Christin

AU - Peng, David

AU - Antonia, Scott

AU - Mediavilla-Varela, Melanie

AU - Robertson, Gordon

AU - Jones, Steve

AU - Suraokar, Milind

AU - Welsh, James W.

AU - Erez, Baruch

AU - Wistuba, Ignacio I.

AU - Chen, Lieping

AU - Peng, Di

AU - Wang, Shanshan

AU - Ullrich, Stephen E.

AU - Heymach, John V.

AU - Kurie, Jonathan M.

AU - Qin, F. Xiao Feng

PY - 2014/10/28

Y1 - 2014/10/28

N2 - 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.

AB - 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.

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

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