Aerosol 1,25-dihydroxyvitamin D3 supplementation: A strategy to boost anti-tumor innate immune activity

Abstract

Background 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] plays a role in calcium homeostasis but can also exert immunomodulatory effects. In lungs, characterized by a particular immunosuppressive environment primarily due to the presence of alveolar macrophages (AM), 1,25(OH)2D3 has been shown to favor the immune response against pathogens. Here, we explored the ability of aerosolized 1,25(OH)2D3 to locally promote an anti-tumor phenotype in alveolar macrophages (AM) in the treatment of lung metastases. Methods Cytotoxicity assay has been used to assess the capability of AM, in vitro treated of not with 1,25(OH)2D3, to stimulate NK cells. Sulforhodamine B (SRB) assay has been used to assess the effect of 1,25(OH)2D3 on MC-38 and B16 tumor cells in vitro growth. 1,25(OH)2D3 was aerosolized in immunocompetent mouse models to evaluate the effect of local administration of 1,25(OH)2D3 on in vivo growth of MC-38 and B16 tumor cells within lungs and on infiltrating immune cells. Results In vitro incubation of naïve AM with 1,25(OH)2D3 improved their ability to stimulate NK cell cytotoxicity. In vivo aerosolized 1,25(OH)2D3 significantly reduced the metastatic growth of MC-38 colon carcinoma, a tumor histotype that frequently metastasizes to lung in human. Immune infiltrate obtained from digested lungs of 1,25(OH)2D3-treated mice bearing MC-38 metastases revealed an increased expression of MHCII and CD80 on AM and an up-modulation of CD69 expression on effector cells that paralleled a strong increased ability of these cells to kill MC-38 tumor in vitro. Conclusions Together, these data show that aerosol delivery can represent a feasible and novel approach to supplement 1,25(OH)2D3 directly to the lungs promoting the activation of local immunity against cancer.

Cigarette smoke sustains immunosuppressive microenvironment inducing M2 macrophage polarization and viability in lung cancer settings

“…Innate immune cells are crucial to mount and sustain a proper anti-tumor immune response and, indeed, many therapeutic strategies aimed at boosting innate immune cells anticancer activity have been explored [56][57][58], such as the use of Toll-like receptors (TLRs) agonists for the success of currently proposed immunotherapy agents in lung cancer, especially immune-check points inhibitors [59,60]. Besides several strategies we and others explored to boost anti-tumor innate immune activity [61]. For instance, Ligands of innate immunity, such as the Toll-like receptors (TLRs) [62], play a crucial role in changing the profile of macrophages and molding the anti-tumor activity of innate immune populations [63][64][65].…”

Vitamin D-Related risk factors for preterm and full-term infants at birth: A retrospective study in Wuxi, China

“…Vitamin D plays an important role in intestinal absorption of calcium and maintenance of bone mineralization [1] , and vitamin D de ciency is a risk factor of rickets and chondropathy in children [2][3][4] . Beyond the well-known skeletal effects, vitamin D has been found to be involved in regulation of innate immune and anti-tumor activity [5][6][7] . Vitamin D de ciency is also associated with many chronic diseases including autoimmune diseases, allergies and asthma which are common clinical problems in infants and young children [8][9][10][11] .…”

Protective effects of inhaled antioxidants against air pollution-induced pathological responses

“…In addition to the study from Serré et al, two other studies have investigated inhaled vitamin D. The studies did not involve pollutant exposure and instead looked at the ability of vitamin D to enhance neonatal lung maturation and to promote anti-tumor immune activity, where it was also found that despite exhibiting therapeutic effects in the lung, treatment did not affect serum levels of vitamin D or calcium, indicating inhaled vitamin D most likely does not pass through the epithelial membrane or cause hypercalcemia [ 16 , 34 , 35 ]. Mathyssen et al expanded on this by examining the transcriptional profile of vitamin D associated enzymes in lung tissue [ 36 ].…”