Phase IB study of 25-hydroxyvitamin D(3) treatment to diminish suppressor cells in head and neck cancer patients.

Patients with head and neck squamous cell carcinoma (HNSCC) have profound immune defects. These defects are associated with a poor prognosis and are mediated, in part, by an increased number of immune inhibitory CD34(+) progenitor cells in their peripheral blood and tumor. The CD34(+) cells suppress autologous T-cell functions. Our prior work had shown that the differentiation inducer 1alpha,25-dihydroxyvitamin D(3) could drive the differentiation of CD34(+) cells isolated from HNSCC patients into dendritic cells. A phase IB clinical trial was initiated with HNSCC patients to determine if 25-hydroxyvitamin D(3) treatment could diminish CD34(+) cell levels and improve immune function. Six patients per treatment group were orally administered 20 or 40 microg/day 25-hydroxyvitamin D(3) for six weeks. Peripheral blood was collected at 0, 1, 2, 4, 6, and 8 weeks, and assessed for markers of immune activity. Although no clinical responses were observed, results of these pilot studies showed that 25-hydroxyvitamin D(3) reduced the presence of immune suppressive CD34(+) cells and improved immune competence of HNSCC patients.

Impact of aging on immune modulation by tumor.

Tumor development and aging can each alter immune competence. The present study aimed to determine the impact of Lewis lung carcinoma (LLC) presence on immune parameters of middle-aged (averaging 6.5 months) versus aged (averaging 21.3 months) mice. An age-associated decline in the CD4+ cell frequency was seen in freshly isolated spleen and lymph node cells, as well as in cultures stimulated with immobilized anti-CD3. This decline was not further exacerbated by tumor presence. What was prominently inhibited by tumor was the capacity of either splenic or lymph node CD4+ cells to become stimulated to express IFN-gamma. Spleen and lymph node cultures from aged tumor-bearing mice had the lowest frequency of CD4+IFN-gamma+ cells and the least amount of secreted IFN-gamma. CD8+ cells were not affected by aging, but tumor presence reduced the induction of CD8+IFN-gamma+ cells in lymph node cultures. We previously showed that LLC growth stimulates myelopoiesis, as seen by splenomegaly and the mobilization of immune inhibitory CD34+ progenitor cells. Tumor presence in middle-aged mice reduced spleen cell blastogenesis, which was mediated by CD34+ cells. Aged mice had reduced blastogenesis, and this was further reduced by presence of tumor. However, neither the age-associated immune dysfunction nor the tumor-induced immune suppression in aged mice was due to CD34+ progenitor cells. These studies show how tumor presence can further compromise the immune dysfunction that accompanies aging. In addition, they show that aging impacts on the mechanisms by which tumors inhibit T-cell capabilities, with myelopoiesis-associated CD34+ cells mediating the immune depression of middle-aged tumor-bearers and an independent mechanism being responsible for the immune depression in aged tumor-bearing mice.