Abstract
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 D3 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 E2, 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 D3 analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications.
Highlights
Due to the lack of an effective treatment for pancreatic cancer, the five-year survival rate has only increased from 3 to 9% since the mid-1970s1
We first examined the expression of the vitamin D receptor (VDR), and in line with the results of others[15], the VDR was expressed in the isolated cancer-associated fibroblasts (CAFs) (Fig. 1a)
To evaluate whether the CAFs were able to respond to the synthetic vitamin D3 derivate calcipotriol, we measured the relative mRNA expression of the VDR target gene CYP24A1 in response to the vitamin D3 analogue
Summary
Due to the lack of an effective treatment for pancreatic cancer, the five-year survival rate has only increased from 3 to 9% since the mid-1970s1. (Middle) expression of αSMA in CAFs treated with either DMSO control, calcipotriol, (n = 11) TGFβ (open circle) or TGFβ together with calcipotriol (blue open circle) (n = 8) in 2D cultures. (Right) representative flow cytometry dot plots of αSMA expression with different treatments is shown. (d) (Left) expression of α-SMA in CAFs cultured in 2D or 3D models treated with either DMSO control or calcipotriol (n = 13). (Right) immunostaining of the 3D models showing αSMA expression in CAFs (in red) co-cultured with PANC-1 spheroids (in blue) is shown. (f) (Left) expression of podoplanin in CAFs cultured in 2D or 3D models treated with either DMSO control or calcipotriol (n = 13). The immunosuppressive role of vitamin D 3 and the downstream interactions between immune cells, cancer cells and the stroma in this setting remain elusive
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