Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFNγ-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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| Format: | Article |
| Language: | English |
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The Royal Society
2022-11-01
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| Series: | Royal Society Open Science |
| Subjects: | |
| Online Access: | https://royalsocietypublishing.org/doi/10.1098/rsos.220186 |
| _version_ | 1797845333378596864 |
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| author | Gerhard A. Burger Daphne N. Nesenberend Carlijn M. Lems Sander C. Hille Joost B. Beltman |
| author_facet | Gerhard A. Burger Daphne N. Nesenberend Carlijn M. Lems Sander C. Hille Joost B. Beltman |
| author_sort | Gerhard A. Burger |
| collection | DOAJ |
| description | 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 (IFNγ)-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 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. In addition, bidirectional crosstalk between miR-200 and PD-L1 implies that IFNγ stimulation allows cells to undergo EMT for lower amounts of inducing signal, and the presence of IFNγ 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. |
| first_indexed | 2024-04-09T17:37:20Z |
| format | Article |
| id | doaj.art-6edede50723c4ababccedebc21d93206 |
| institution | Directory Open Access Journal |
| issn | 2054-5703 |
| language | English |
| last_indexed | 2024-04-09T17:37:20Z |
| publishDate | 2022-11-01 |
| publisher | The Royal Society |
| record_format | Article |
| series | Royal Society Open Science |
| spelling | doaj.art-6edede50723c4ababccedebc21d932062023-04-17T10:54:42ZengThe Royal SocietyRoyal Society Open Science2054-57032022-11-0191110.1098/rsos.220186Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumour progressionGerhard A. Burger0Daphne N. Nesenberend1Carlijn M. Lems2Sander C. Hille3Joost B. Beltman4Division of Drug Discovery and Safety, Leiden University, Leiden, The NetherlandsDivision of Drug Discovery and Safety, Leiden University, Leiden, The NetherlandsDivision of Drug Discovery and Safety, Leiden University, Leiden, The NetherlandsMathematical Institute, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The NetherlandsDivision of Drug Discovery and Safety, Leiden University, Leiden, The NetherlandsEpithelial–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 (IFNγ)-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 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. In addition, bidirectional crosstalk between miR-200 and PD-L1 implies that IFNγ stimulation allows cells to undergo EMT for lower amounts of inducing signal, and the presence of IFNγ 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.https://royalsocietypublishing.org/doi/10.1098/rsos.220186epithelial-mesenchymal transition (EMT)immune evasionPD-L1interferon gamma |
| spellingShingle | Gerhard A. Burger Daphne N. Nesenberend Carlijn M. Lems Sander C. Hille Joost B. Beltman Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumour progression Royal Society Open Science epithelial-mesenchymal transition (EMT) immune evasion PD-L1 interferon gamma |
| title | Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumour progression |
| title_full | Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumour progression |
| title_fullStr | Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumour progression |
| title_full_unstemmed | Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumour progression |
| title_short | Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumour progression |
| title_sort | bidirectional crosstalk between epithelial mesenchymal plasticity and ifnγ induced pd l1 expression promotes tumour progression |
| topic | epithelial-mesenchymal transition (EMT) immune evasion PD-L1 interferon gamma |
| url | https://royalsocietypublishing.org/doi/10.1098/rsos.220186 |
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