4.7 Article

The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity

Journal

SCIENTIFIC REPORTS
Volume 10, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41598-020-74368-3

Keywords

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Funding

  1. Karolinska Institute
  2. Cancer Society in Stockholm [171083]
  3. Swedish Cancer Foundation [CAN 2017/749]
  4. Ruth and Richard Julin's Foundation
  5. Cancer and Allergy Foundation [282]
  6. Karolinska Institutet
  7. Robert Lundberg's Foundation

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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-gamma, 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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