Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status
Epithelial-mesenchymal transition (EMT) and immune resistance mediated by Programmed Death-Ligand 1 (PD-L1) upregulation are established drivers of tumor progression. Their bi-directional crosstalk has been proposed to facilitate tumor immunoevasion, yet the impact of immunosuppression and spatial h...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1219669/full |
| _version_ | 1797745429025128448 |
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| author | Carlijn M. Lems Gerhard A. Burger Joost B. Beltman |
| author_facet | Carlijn M. Lems Gerhard A. Burger Joost B. Beltman |
| author_sort | Carlijn M. Lems |
| collection | DOAJ |
| description | Epithelial-mesenchymal transition (EMT) and immune resistance mediated by Programmed Death-Ligand 1 (PD-L1) upregulation are established drivers of tumor progression. Their bi-directional crosstalk has been proposed to facilitate tumor immunoevasion, yet the impact of immunosuppression and spatial heterogeneity on the interplay between these processes remains to be characterized. Here we study the role of these factors using mathematical and spatial models. We first designed models incorporating immunosuppressive effects on T cells mediated via PD-L1 and the EMT-inducing cytokine Transforming Growth Factor beta (TGFβ). Our models predict that PD-L1-mediated immunosuppression merely reduces the difference in PD-L1 levels between EMT states, while TGFβ-mediated suppression also causes PD-L1 expression to correlate negatively with TGFβ within each EMT phenotype. We subsequently embedded the models in multi-scale spatial simulations to explicitly describe heterogeneity in cytokine levels and intratumoral heterogeneity. Our multi-scale models show that Interferon gamma (IFNγ)-induced partial EMT of a tumor cell subpopulation can provide some, albeit limited protection to bystander tumor cells. Moreover, our simulations show that the true relationship between EMT status and PD-L1 expression may be hidden at the population level, highlighting the importance of studying EMT and PD-L1 status at the single-cell level. Our findings deepen the understanding of the interactions between EMT and the immune response, which is crucial for developing novel diagnostics and therapeutics for cancer patients. |
| first_indexed | 2024-03-12T15:23:10Z |
| format | Article |
| id | doaj.art-cc17b7a0b83a4c5bbcf5d006a6bb64cc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T15:23:10Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-cc17b7a0b83a4c5bbcf5d006a6bb64cc2023-08-10T23:05:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-08-011410.3389/fimmu.2023.12196691219669Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 statusCarlijn M. LemsGerhard A. BurgerJoost B. BeltmanEpithelial-mesenchymal transition (EMT) and immune resistance mediated by Programmed Death-Ligand 1 (PD-L1) upregulation are established drivers of tumor progression. Their bi-directional crosstalk has been proposed to facilitate tumor immunoevasion, yet the impact of immunosuppression and spatial heterogeneity on the interplay between these processes remains to be characterized. Here we study the role of these factors using mathematical and spatial models. We first designed models incorporating immunosuppressive effects on T cells mediated via PD-L1 and the EMT-inducing cytokine Transforming Growth Factor beta (TGFβ). Our models predict that PD-L1-mediated immunosuppression merely reduces the difference in PD-L1 levels between EMT states, while TGFβ-mediated suppression also causes PD-L1 expression to correlate negatively with TGFβ within each EMT phenotype. We subsequently embedded the models in multi-scale spatial simulations to explicitly describe heterogeneity in cytokine levels and intratumoral heterogeneity. Our multi-scale models show that Interferon gamma (IFNγ)-induced partial EMT of a tumor cell subpopulation can provide some, albeit limited protection to bystander tumor cells. Moreover, our simulations show that the true relationship between EMT status and PD-L1 expression may be hidden at the population level, highlighting the importance of studying EMT and PD-L1 status at the single-cell level. Our findings deepen the understanding of the interactions between EMT and the immune response, which is crucial for developing novel diagnostics and therapeutics for cancer patients.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1219669/fullepithelial-mesenchymal transition (EMT)PD-L1immunoevasionordinary differential equationscellular Potts model |
| spellingShingle | Carlijn M. Lems Gerhard A. Burger Joost B. Beltman Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status Frontiers in Immunology epithelial-mesenchymal transition (EMT) PD-L1 immunoevasion ordinary differential equations cellular Potts model |
| title | Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status |
| title_full | Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status |
| title_fullStr | Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status |
| title_full_unstemmed | Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status |
| title_short | Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status |
| title_sort | tumor mediated immunosuppression and cytokine spreading affects the relation between emt and pd l1 status |
| topic | epithelial-mesenchymal transition (EMT) PD-L1 immunoevasion ordinary differential equations cellular Potts model |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1219669/full |
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