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 D3. Therefore, studies determined whether vitamin D3 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 D3 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 D3 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 D3 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 D3 treatment increases intratumoral T-cell immune reactivity, and that coupling vitamin D3 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.

1alpha,25-dihydroxyvitamin D3 activates T cells of tumor bearers through protein phosphatase 2A.

The sterol 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] can inhibit T cell activation as well as restore the functional competence of suppressed T cells, The present studies determined whether 1,25(OH)2D3 had a differential effect on the activation of normal T cells or of suppressed T cells from mice bearing Lewis lung carcinoma tumors. Normal spleen cell proliferation in response to immobilized anti-CD3 was unaffected by the lower doses of 0.1-10 nM 1,25(OH)2D3, and was inhibited by the higher dose of 100 nM 1,25(OH)2D3. In contrast, 1,25(OH)2D3 increased proliferation and interferon gamma secretion by T cells of tumor bearers in response to stimulation through T cell receptor/CD3. Assessment of mechanisms associated with the 1,25(OH)2D3 stimulation of tumor-bearer T cells implicated protein phosphatase 2A (PP-2A). First, PP-2A activity of spleen cells from tumor bearers was reduced compared to that of normal spleen cells but was increased by 1,25(OH)2D3. Second, 1,25(OH)2D3 stimulation of tumor-bearer T cell proliferation was dependent on this PP-2A activity as it was blocked by doses of okadaic acid that selectively inhibit PP-2A. These results suggest that 1,25(OH)2D3 preferentially enhances the responsiveness of immunosuppressed T cells from tumor bearers to TCR/CD3 stimulation by restoring PP-2A activity.