Vitamin D-3 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 functio n. Using a metastatic Lewis lung carcinoma (LLC-LN7) tumor model, these CD3 4(+) 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 cel l differentiation, vitamin D-3. Therefore, studies determined whether vitam in 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 intratu moral 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 w ith the combination of vitamin D-3 and adoptive immunotherapy significantly reduced metastasis in mice with established tumors, and reduced both metas tasis and locoregional recurrence after surgical excision of the primary tu mor. These studies demonstrate that vitamin D-3 treatment increases intratu moral T-cell immune reactivity, and that coupling vitamin D-3 treatment to diminish levels of CD34(+) NS cells with adoptive immunotherapy enhances th e effectiveness of the adoptively transferred tumor-reactive lymph node cel ls at limiting both metastasis and locoregional tumor recurrence.