Bidirectional crosstalk between epithelial-mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumor 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, the 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{gamma})-induced PD-L1 expression. Our model shows that via interaction with microRNA-200 (miR-200), the multistability of the EMT regulatory circuit is mirrored in the PD-L1 levels, which are further amplified by IFN{gamma} stimulation. This IFN{gamma}-mediated effect is most prominent for cells in a fully mesenchymal state, and less strong for those in an epithelial or partially mesenchymal state. Additionally, bi-directional crosstalk between miR-200 and PD-L1 implies that IFN{gamma} stimulation allows cells to undergo EMT for lower amounts of inducing signal, and that IFN{gamma} presence 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/478950v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1e5fde0org.highwire.dtl.DTLVardef@7e929dorg.highwire.dtl.DTLVardef@1cb9f6borg.highwire.dtl.DTLVardef@14f50ad_HPS_FORMAT_FIGEXP M_FIG C_FIG Schematic overview of the crosstalk between Epithelial-Mesenchymal Transition (EMT) and Interferon gamma (IFN{gamma})-induced Programmed Death-Ligand 1 (PD-L1) expression. IFN{gamma}-induced PD-L1 expression promotes the occurrence of EMT. EMT, also induced by, for example, Transforming Growth Factor Beta (TGF{beta}), increases PD-L1 expression levels, facilitating tumor immunoevasion.