Bidirectional crosstalk between epithelial-mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumor progression

bioRxiv (Cold Spring Harbor Laboratory)

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 (IFNγ)-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 IFNγ stimulation. This IFNγ-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 IFNγ stimulation allows cells to undergo EMT for lower amounts of inducing signal, and that IFNγ 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.

Authors 5

1. Gerhard A. Burger Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

2. Daphne Nesenberend Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research Mathematical Institute

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

   Mathematical Institute, Leiden University, Leiden, The Netherlands

3. Carlijn M. Lems Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

4. Sander C. Hille Aachen Mathematical Institute

   Leiden University

   Affiliation as printed

   Mathematical Institute, Leiden University, Leiden, The Netherlands

5. Joost B. Beltman corresponding Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands