Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFN γ -induced PD-L1 expression promotes tumour progression

Epithelial–mesenchymal transition (EMT) and immunoevasion through upregulation of programmed death-ligand 1 (PD-L1) are important drivers of cancer progression. While EMT has been proposed to facilitate PD-L1-mediated immunosuppression, molecular mechanisms of their interaction remain obscure. Here,...

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Bibliographic Details
Published in:Royal Society open science Vol. 9; no. 11; p. 220186
Main Authors: Burger, Gerhard A., Nesenberend, Daphne N., Lems, Carlijn M., Hille, Sander C., Beltman, Joost B.
Format: Journal Article
Language:English
Published: The Royal Society 02.11.2022
Subjects:
Biochemistry, Cellular and Molecular Biology
epithelial-mesenchymal transition (EMT)
immune evasion
interferon gamma
PD-L1
ISSN:2054-5703, 2054-5703
Online Access:Get full text
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Summary:Epithelial–mesenchymal transition (EMT) and immunoevasion through upregulation of programmed death-ligand 1 (PD-L1) are important drivers of cancer progression. While EMT has been proposed to facilitate PD-L1-mediated immunosuppression, molecular mechanisms of their interaction remain obscure. Here, we provide insight into these mechanisms by proposing a mathematical model that describes the crosstalk between EMT and interferon gamma (IFN γ )-induced PD-L1 expression. Our model shows that via interaction with microRNA-200 (miR-200), the multi-stability of the EMT regulatory circuit is mirrored in PD-L1 levels, which are further amplified by IFN γ stimulation. This IFN γ -mediated effect is most prominent for cells in a fully mesenchymal state and less strong for those in an epithelial or partially mesenchymal state. In addition, bidirectional crosstalk between miR-200 and PD-L1 implies that IFN γ stimulation allows cells to undergo EMT for lower amounts of inducing signal, and the presence of IFN γ accelerates EMT and decelerates mesenchymal–epithelial transition (MET). Overall, our model agrees with published findings and provides insight into possible mechanisms behind EMT-mediated immune evasion, and primary, adaptive, or acquired resistance to immunotherapy. Our model can be used as a starting point to explore additional crosstalk mechanisms, as an improved understanding of these mechanisms is indispensable for developing better diagnostic and therapeutic options for cancer patients.
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Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.6251541.
These authors have contributed equally to this work.
ISSN:2054-5703
2054-5703
DOI:10.1098/rsos.220186