Abstract
Combined approaches based on immunotherapy and drugs supporting immune effector cell function might increase treatment options for pancreatic ductal adenocarcinoma (PDAC), vitamin D being a suitable drug candidate. In this study, we evaluated whether treatment with the vitamin D analogue, calcipotriol, counterbalances PDAC induced and SMAD4-associated intracellular calcium [Ca2+]i alterations, cytokines release, immune effector function, and the intracellular signaling of peripheral blood mononuclear cells (PBMCs). Calcipotriol counteracted the [Ca2+]i depletion of PBMCs induced by SMAD4-expressing PDAC cells, which conditioned media augmented the number of calcium flows while reducing whole [Ca2+]i. While calcipotriol inhibited spontaneous and PDAC-induced tumor necrosis factor alpha (TNF-α) release by PBMC and reduced intracellular transforming growth factor beta (TGF-β), it did not counteract the lymphocytes proliferation induced in allogenic co-culture by PDAC-conditioned PBMCs. Calcipotriol mainly antagonized PDAC-induced apoptosis and partially restored PDAC-inhibited NF-κB signaling pathway. In conclusion, alterations induced by PDAC cells in the [Ca2+]i of immune cells can be partially reverted by calcipotriol treatment, which promotes inflammation and antagonizes PBMCs apoptosis. These effects, together with the dampening of intracellular TGF-β, might result in an overall anti-tumor effect, thus supporting the administration of vitamin D in PDAC patients.
Highlights
The known ability of the tumor microenvironment to influence tumor cell behavior appears to be of particular relevance in the fourth worldwide cause of cancer-related death, pancreatic ductal adenocarcinoma (PDAC), which is characterized by dense desmoplasia with dispersed immune cells, cancer associated fibroblasts (CAFs), and pancreatic stellate cells (PSCs)
Whole and peak intracellular calcium areas were significantly reduced in untreated peripheral blood mononuclear cells (PBMCs) after 3 days, with respect to 2 days of culture, while the number of intracellular calcium peaks significantly decreased after 4 days in untreated, and after 3 days in treated, PBMCs
Pancreatic cancer cell line-conditioned media caused different alterations in the intracellular calcium of PBMCs depending on the presence or complete absence of SMAD4 gene: in the presence of SMAD4, the PDAC conditioned media induced an increase in the number of calcium peaks and a reduction in the whole intracellular calcium (Table 2)
Summary
The known ability of the tumor microenvironment to influence tumor cell behavior appears to be of particular relevance in the fourth worldwide cause of cancer-related death, pancreatic ductal adenocarcinoma (PDAC), which is characterized by dense desmoplasia with dispersed immune cells, cancer associated fibroblasts (CAFs), and pancreatic stellate cells (PSCs). Since PDAC-associated immunosuppression concurs in reducing survival, the depletion of immunosuppressive cells and/or the restoration of immune effector cells might be effective strategies for improving outcome and be useful in treatments targeting molecules and pathways involved in immune cell regulation, such as those using checkpoint inhibitors with antibodies anti-CTLA4 or anti PD1/PDL1 [3]. As yet, these treatment strategies have proven disappointing in humans, and the factors underlying their failure are not well understood. A suitable candidate in this context appears to be vitamin D, which has been the object of intensive research in cancer, including PDAC, studies focusing on the role of vitamin D in cancer prevention on the one hand, and cancer treatment on the other [4]
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