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

Abstract

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.

Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status

“…To study how this negative feedback of PD-L1 on IFNγ production affects the relationship between EMT and IFNγ-induced PD-L1 expression, we extended the model of Burger et al. ( 19 ) with this regulation ( Figure 1A , red, dashed arrow).…”

“…In the present study, we extended the model presented by Burger et al. ( 19 ) to explore the role of immunosuppression through PD-L1 or TGFβ, and of intratumoral heterogeneity on the crosstalk between EMT and PD-L1 expression. Analysis of our models with immunosuppression shows that negative feedback of PD-L1 on IFNγ only decreases the difference in PD-L1 expression between EMT phenotypes, whereas TGFβ-mediated IFNγ inhibition gives rise to a negative correlation between TGFβ and PD-L1 levels within EMT phenotypes.…”

“…The binding of miR-200 to PD-L1 mRNA inhibits translation of the checkpoint ligand, and such binding can generally promote degradation of the miRNA–mRNA complex ( 17 , 18 ). To investigate this mechanism, we recently presented a mathematical model connecting a model for the core EMT network to a model for IFNγ-induced PD-L1 expression ( 19 ), considering mutual inhibitory feedback between miR-200 and PD-L1. Model analysis showed that this interaction gives rise to tristability in PD-L1 levels, with a mesenchymal state corresponding with high PD-L1 expression, an epithelial state with low PD-L1 expression, and an E/M state with intermediate (albeit still relatively low) PD-L1 expression.…”

“…Despite displaying interesting dynamics relevant for tumor progression, our prior model of EMT–PD-L1 dynamics ( 19 ) did not take into account several mechanisms and factors affecting EMT and PD-L1 expression. First, an important missing mechanism was the negative feedback of PD-L1 on the IFNγ secretion of T cells, which results from the PD-L1–PD-1 interaction ( 20 ).…”

Targeting the immune microenvironment for ovarian cancer therapy

“…When it binds to its receptor PD-1, mainly present on lymphocytes, it generates an inhibitory signal ( 150 ). Importantly, PD-L1 expression on TILS can be induced by various factors secreted by TILS themselves or NK cells, such as IFNγ ( 151 , 152 ). OC infiltrating DCs and MDSCs can also express both PD-1 and PD-L1 on their surface, promoting T-cell exhaustion ( 105 , 121 ).…”