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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...

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Autores principales: Gorchs, Laia, Ahmed, Sultan, Mayer, Chanté, Knauf, Alisa, Fernández Moro, Carlos, Svensson, Mattias, Heuchel, Rainer, Rangelova, Elena, Bergman, Peter, Kaipe, Helen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
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.
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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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