Progressive growth of metastatic Lewis lung carcinoma (LLC-LN7) tumors is associated with increased levels of bone-marrow-derived CD34+ cells having natural suppressor (NS) activity toward T cells. The present studies determined whether tumor-derived products are responsible for this induction of NS activity. Culturing normal bone marrow cells with LLC-LN7-conditioned medium (LLC-CM) or with recombinant granulocyte/macrophage-colony-stimulating factor (GM-CSF) resulted in the appearance of NS activity. The development of NS activity coincided with a prominent increase in the levels of CD34+ cells. That the CD34+ cells were responsible for the NS activity of the bone marrow cultures containing LLC-CM was shown by the loss of NS activity when CD34+ cells were depleted. The stimulation of CD34+ NS cells by LLC-CM was attributed to tumor production of GM-CSF, since neutralization of GM-CSF within the LLC-CM reduced its capacity to increase CD34+ cell levels. Studies also showed that the induction of CD34+ NS cells by LLC-CM and GM-CSF could be overcome by including in the cultures an inducer of myeloid differentiation, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. These results demonstrate that the mechanism by which the LLC-LN7 tumors stimulate increased levels of CD34+ NS cells from normal bone marrow is by their production of GM-CSF and that this can be blocked with the myeloid differentiation inducer 1,25(OH)2D3.
Growth of Lewis lung carcinoma (LLC-LN7) tumors results in an increase in CD34+ granulocyte-macrophage progenitor cells having natural suppressor (NS) activity. These CD34+ NS cells were capable of inhibiting the cytotoxic activity of tumor-reactive lymph node cells. In vivo studies showed that adoptive treatment of LLC-LN7 tumor-bearing mice with tumor-reactive lymph node cells plus IL-2 failed to reduce the development of metastases. Studies were conducted to determine if diminishing the levels of CD34+ NS cells would allow for improved anti-tumor effectiveness of the adoptively transferred cells. The suppressive activity of CD34+ cells toward the cytolytic activity of tumor-reactive lymph node cells could be blocked by in vitro culture of CD34+ cells with the differentiation-inducing hormone 1alpha,25-dihydroxyvitamin D3. Similarly, treatment of LLC-LN7-bearing mice with vitamin D3 alone diminished the levels of CD34+ NS cells within regional lymph nodes, spleens and tumors. This treatment resulted in an increased immune reactivity to autologous tumor, as shown by the production of IFN-gamma by lymph node cells in response to the presence of LLC-LN7 cells. The extent of tumor metastasis in mice receiving vitamin D3 treatment was also reduced. When tumor-reactive lymph node cells were adoptively transferred into these LLC-LN7-bearing mice that were receiving vitamin D3 treatment, there resulted a pronounced synergistic reduction in tumor metastasis. The results of this study show that treatment of tumor bearers with vitamin D3 to eliminate CD34+ NS cells improves the anti-tumor effectiveness of adoptively transferred tumor-reactive lymph node cells.
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