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

Abstract

Immunosuppression of tumor-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 tumor 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.

Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma

“…Co-enrichment of these signatures, collectively referred to as the Innate anti-PD-1 Resistance or IPRES signature, again indicated heightened mesenchymal transition, angiogenesis, hypoxia and wound healing. The concurrence of a tumor cell mesenchymal phenotype with an angiogenesis-and wound healing-related inflammatory microenvironment has been documented in the literature (Chen et al, 2015a;Chen et al, 2015b;Mak et al, 2015). Interestingly, this set of 26 IPRES signatures included signatures induced by MAPK inhibitor (MAPKi) treatment of melanoma tumors and cell lines (Table S2C).…”

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…Chen et al [131] demonstrated that miR-200 suppressed the epithelial to mesenchymal transition (EMT) process by targeting PD-L1 and thus delaying cancer progression in a mouse model. As shown before, miR-200 expression is downregulated in highly metastatic cancer cells [132,133].…”

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

“…117,118 Iliopoulos et al 119 demonstrated that miR-21 expression was upregulated by ovalbumin stimulation in T cells and also that the inhibition of PD-1 increased miR-21 expression. Chen et al 120 suggested that a relationship exists between miR-200 and PD-L1 expression in human lung cancer. Furthermore, previous studies have indicated that a relationship exists between these immune checkpoints and a number of miRNA; however, these relationships have not yet been elucidated in detail.…”