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

L Chen, DL Gibbons, S Goswami, MA Cortez… - Nature …, 2014 - nature.com
L Chen, DL Gibbons, S Goswami, MA Cortez, YH Ahn, LA Byers, X Zhang, X Yi, D Dwyer…
Nature communications, 2014nature.com
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 …
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.
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