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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10449452/ https://www.ncbi.nlm.nih.gov/pubmed/37638024 http://dx.doi.org/10.3389/fimmu.2023.1219669 |
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author | Lems, Carlijn M. Burger, Gerhard A. Beltman, Joost B. |
author_facet | Lems, Carlijn M. Burger, Gerhard A. Beltman, Joost B. |
author_sort | Lems, Carlijn M. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-10449452 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-104494522023-08-25 Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status Lems, Carlijn M. Burger, Gerhard A. Beltman, Joost B. Front Immunol Immunology 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. Frontiers Media S.A. 2023-08-10 /pmc/articles/PMC10449452/ /pubmed/37638024 http://dx.doi.org/10.3389/fimmu.2023.1219669 Text en Copyright © 2023 Lems, Burger and Beltman https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Lems, Carlijn M. Burger, Gerhard A. Beltman, Joost B. Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status |
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 | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10449452/ https://www.ncbi.nlm.nih.gov/pubmed/37638024 http://dx.doi.org/10.3389/fimmu.2023.1219669 |
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