Vitamin D3 treatment to diminish the levels of immune suppressive CD34+ cells increases the effectiveness of adoptive immunotherapy

Tumor growth can increase the number of immature bone marrow-derived CD34(+) cells that exhibit natural suppressor (NS) activity toward T-cell function. Using a metastatic Lewis lung carcinoma (LLC-LN7) tumor model, these CD34(+) NS cells were shown to be present within the s.c. primary tumor tissue, but their levels declined after treatment with the inducer of myeloid cell differentiation, vitamin D-3. Therefore, studies determined whether vitamin D-3 treatment to diminish the CD34(+) NS cell levels in LLC-LN7-bearing mice would enhance (a) intratumoral immune reactivity and (b) the antitumor activity of adoptive therapy consisting of tumor-reactive lymph node cells. The results showed that vitamin D-3 treatment alone increased the intratumoral CD8(+) cell content and the activity of the intratumoral infiltrate, as detected by production of interferon-gamma and expression of the p55 IL-2 receptor. Although vitamin D-3 treatment had no effect on the size of the primary tumor, it lessened the extent of tumor metastasis. Treating mice with the combination of vitamin D-3 and adoptive immunotherapy significantly reduced metastasis in mice with established tumors, and reduced both metastasis and locoregional recurrence after surgical excision of the primary tumor. These studies demonstrate that vitamin D-3 treatment increases intratumoral T-cell immune reactivity, and that coupling vitamin D-3 treatment to diminish levels of CD34(+) NS cells with adoptive immunotherapy enhances the effectiveness of the adoptively transferred tumor-reactive lymph node cells at limiting both metastasis and locoregional tumor recurrence.