Metastasis is regulated via microRNA-200/ZEB1 axis control of tumor cell PD-L1 expression and intratumoral immunosuppression
By Limo Chen, D. Gibbons, S. Goswami, M. Cortez, Young‐Ho Ahn, L. Byers, Xuejun Zhang, X. Yi, David W. Dwyer, Wei Lin and 21 more. Nature Communications, 2014
900 citations recorded by the source corpus.
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. Tumour-infiltrating lymphocytes (TILs) can be suppressed by the tumour, but how this occurs is not clear. Here the authors show that the miR-200 family, which suppresses epithelial–mesenchymal transition, also targets tumour cell PD-L1 and thereby intratumoral immunosuppression and metastasis.
Subfields: Cancer Research, Oncology
View Paper: https://www.semanticscholar.org/paper/6a204afbbe2728ebf20dc1809d284629ebfc3123
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Citations in the corpus
- Regulation of PD-L1: a novel role of pro-survival signalling in cancer. (2016, background): “It has been demonstrated that PD-L1 upregulation due to decreased miR-200, results in dysfunction of CD8 T-cells, which coupled with epithelial-mesenchymal transition (EMT) to increase metastasis[45].”
- Epithelial-mesenchymal plasticity in cancer progression and metastasis (2019, background): “Additionally, EMT can directly induce the expression of PD-L1 in carcinoma cells (Chen et al., 2014; Noman et al., 2017).”
- Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma (2016, positive): “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).”
- Co-occurring genomic alterations define major subsets of KRAS - mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities (2015, neutral): “Recent preclinical studies from our group and others are consistent with this possibility (47).”
- PDL1 Regulation by p53 via miR-34 (2015, background): “A) Correlation between p53 and PDL1 (CD274) mRNA expression in samples from 181 patients with NSCLC from The Cancer Genome Atlas (TCGA) (P .001) (29).”
- Epithelial-Mesenchymal Plasticity: A central regulator of cancer progression (2015, background): “In lung cancer cells, activation of the EMT-TF Zeb1 has been linked to increases in PD-L1 expression, a known immune-suppressive molecule that can block the attack of tumor-infiltrating lymphocytes (Chen et al., 2014).”
- Mechanisms controlling PD-L1 expression in cancer (2019, background): “By harnessing the IFN-γ/JAK/STAT1 pathway, PDL1 expressed on cancer cells inactivate cytotoxic T cells and attenuate immunosurveillance in the TME.”