There is a critical difference: on MP, a proposed VDR agonist Benicar is used to bind with the receptors, while all above studies therapies/tests are based on VDR agonist
precursors(D3 and D25). The main issue with D25(raised via D3/sun) is that it inducts hyperresponsiveness to bacterial patterns/toxins:
https://www.sciencedaily.com/releases/2012/02/120223103920.htm
Also, D3->D25 immunosuppression favors accelerated tumor growth(by blunting down Th1 immune response):
Vitamin D aggravates breast cancer by inducing immunosuppression in the tumor bearing mouse:
https://www.ncbi.nlm.nih.gov/pubmed/29852828
The aim of this approach is to test the effects and related mechanism of vitamin D (VD) treatment on the outcomes of breast cancer. BALB/c mice were injected with 4T1 breast cancer cell suspension. The test group was treated with VD reagent. The survival and tumor size of mice were observed. The proliferation of 4T1 in vitro was detected by MTS analysis. The changes of immune parameters and microenvironment in mice were evaluated by flow cytometry and real-time RT-PCR. Our results demonstrate that VD administration caused a decline in survival time and raising the volume of tumor, the decreasing numbers of CD3+CD4+ T, CD3+CD8+ T and CD4+T-bet+IFN-γ+ Th1 cells and transcriptions of T-bet and IFN-γ, an increasing number of myeloid-derived suppressor cells and transcription of TGF-β. Our data suggest that the routine clinical application of any strategies targeting VD status for breast cancer therapy is deserved serious consideration.
...
VD accelerated tumor growth & death of mice in 4T1 tumor-bearing mice Seventeen days after BALB/c mice were inoculated with 4T1 mammary carcinoma cells, the transplanted tumor was already obviously to be observed in the mice, then the tumor-bearing mice were orally treated with vehicle control (soybean oil) or VD for 1 week. Tumor growth was periodically measured and animals were monitored for survival outcome. As shown in Figure 2, around 10 days after 4T1 tumor cell inoculation, we can detect the tumor volume. With the time proceeding, the tumor growth showed a significant promotion in VD treatment mouse group. The tumor size in VD-treated group was bigger than the control group from day 31 postinoculation (Figure 2A) (p < 0.05). The survival rate in the VD-treated group was significantly shortened in comparison with that in the control group (Figure 2B). The result showed that VD could accelerate tumor growth and significantly shorten the survival of 4T1 tumor-bearing mice. On day 8 post VD treatment, we detected the concentrations of VD and calcium in the tumor-bearing mouse sera. The concentration of VD(detected as 25(OH)-Vitamin D)was higher than that of control group (p < 0.05), whereas the concentration of calcium had no difference in these two groups. The results were shown in Figure 3A & B.
VD treatment inhibited the systemic immune response in 4T1 tumor-bearing mice.
CD8+ cytotoxic T cells and Th1 cells curb cancer development via mechanisms commonly involving their production of cytotoxins and IFN-γ. To test whether VD treatment could inhibit the immune response mediated by T cells, we tested the numbers of CD3+CD4+, CD3+CD8+ and CD4+T-bet+IFN-γ+ T cells from splenocytes on day 25 and 32 postinoculation. Day 25 postinoculation marks the end of the VD oral administration. Day 32 postinoculation is the day of 1 week after VD oral administration. On day 32 postinoculation, the numbers of CD3+CD4+ (Figure 5A–C) and CD3+CD8+ (Figure 5D–F) T cells in VD treated group dramatically decreased. However, the Th1 cell and CD4+T-bet+IFN-γ+ cells were decreased on day 25 post inoculation (Figure 5G–I). These results indicated that the VD treatment affected the important T cell subsets proliferation, not only help T cell (CD4+) but also cytotoxic T cell (CD8+). Our data also investigated that the decrease of CD8+ T cells might be related to the Th1 cells, which was inhibited on earlier time.
VD has been increasingly recognized to have regulatory functions on both innate and adaptive immune [34]. The active form of VD (calcitriol [1,25(OH)2D3]) primarily affects DCs maturation and macrophage differentiation [35,36] and inhibits the production of the cytokines, IL-12 and IL-23. In addition, calcitriol directly acts on T cells to inhibit T-cell proliferation and IFN-γ production [37]. Moreover,calcitriol favors development of Tregs via modulation of DCs [38].Our data demonstrate that VD results in a decrease of the Th1 response in both spleen cells and tumor tissue. Also, suppressive cells of the innate arm of the immune system, such as inflammation-induced MDSCs, are known to be correlated with poor outcome and rapid disease progression [39,40]. MDSCs utilize a variety of mechanisms to suppress T-cell activation and induce other immune-suppressive cell populations [24]. On day 32 post inoculation, the number of MDSCs from spleen cells was dramatically increased. This change is consistent with the change of Th1-related cells.
Collectively, these data are in line with earlier descriptions of the suppressive activities of VD with respect to the stimulation of Th1-mediated immunity.
Conclusion & future perspective
In summary, we demonstrate that VD treatment accelerates the growth of breast cancer in mice, which is closely associated with the activation of MDSCs.
VD treatment suppressed the Th1 response in both system and tumor microenvironment. These results indicate that VD application might be associated with worse prognosis and seems to promote tumorigenesis. Therefore, these results would sugggest a thoughtful consideration for the routine application of VD replenishment to breast cancer prevention or therapy.