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The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity
The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D(3) analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dime...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562723/ https://www.ncbi.nlm.nih.gov/pubmed/33060625 http://dx.doi.org/10.1038/s41598-020-74368-3 |
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author | Gorchs, Laia Ahmed, Sultan Mayer, Chanté Knauf, Alisa Fernández Moro, Carlos Svensson, Mattias Heuchel, Rainer Rangelova, Elena Bergman, Peter Kaipe, Helen |
author_facet | Gorchs, Laia Ahmed, Sultan Mayer, Chanté Knauf, Alisa Fernández Moro, Carlos Svensson, Mattias Heuchel, Rainer Rangelova, Elena Bergman, Peter Kaipe, Helen |
author_sort | Gorchs, Laia |
collection | PubMed |
description | The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D(3) analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E(2), IL-6, periostin, and leukemia inhibitory factor. However, calcipotriol promoted PD-L1 upregulation, which could influence T cell mediated tumour immune surveillance. Calcipotriol reduced T cell proliferation and production of IFN-γ, granzyme B and IL-17, but increased IL-10 secretion. These effects were even more profound in the presence of CAFs in 2D cultures and in the presence of CAFs and pancreatic tumour cell line (PANC-1) spheroids in 3D cultures. Functional assays on tumour infiltrating lymphocytes also showed a reduction in T cell activation by calcipotriol. This suggests that calcipotriol reduces the tumour supportive activity of CAFs but at the same time reduces T cell effector functions, which could compromise the patients’ tumour immune surveillance. Thus, vitamin D(3) analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications. |
format | Online Article Text |
id | pubmed-7562723 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75627232020-10-19 The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity Gorchs, Laia Ahmed, Sultan Mayer, Chanté Knauf, Alisa Fernández Moro, Carlos Svensson, Mattias Heuchel, Rainer Rangelova, Elena Bergman, Peter Kaipe, Helen Sci Rep Article The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D(3) analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E(2), IL-6, periostin, and leukemia inhibitory factor. However, calcipotriol promoted PD-L1 upregulation, which could influence T cell mediated tumour immune surveillance. Calcipotriol reduced T cell proliferation and production of IFN-γ, granzyme B and IL-17, but increased IL-10 secretion. These effects were even more profound in the presence of CAFs in 2D cultures and in the presence of CAFs and pancreatic tumour cell line (PANC-1) spheroids in 3D cultures. Functional assays on tumour infiltrating lymphocytes also showed a reduction in T cell activation by calcipotriol. This suggests that calcipotriol reduces the tumour supportive activity of CAFs but at the same time reduces T cell effector functions, which could compromise the patients’ tumour immune surveillance. Thus, vitamin D(3) analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications. Nature Publishing Group UK 2020-10-15 /pmc/articles/PMC7562723/ /pubmed/33060625 http://dx.doi.org/10.1038/s41598-020-74368-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Gorchs, Laia Ahmed, Sultan Mayer, Chanté Knauf, Alisa Fernández Moro, Carlos Svensson, Mattias Heuchel, Rainer Rangelova, Elena Bergman, Peter Kaipe, Helen The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity |
title | The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity |
title_full | The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity |
title_fullStr | The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity |
title_full_unstemmed | The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity |
title_short | The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity |
title_sort | vitamin d analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic cafs but reduces t cell mediated immunity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562723/ https://www.ncbi.nlm.nih.gov/pubmed/33060625 http://dx.doi.org/10.1038/s41598-020-74368-3 |
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