1-ALPHA,25-DIHYDROXYVITAMIN-D3 PLUS GAMMA-INTERFERON BLOCKS LUNG-TUMOR PRODUCTION OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AND INDUCTION OF IMMUNOSUPPRESSOR CELLS

Metastatic Lewis lung carcinoma (LLC-LN7) cells have previously been s hown to produce granulocyte-macrophage colony-stimulating factor (GM-C SF) which induces the appearance of immunosuppressive granulocytic-mac rophage progenitor cells (GM-suppressor cells). The present in vitro s tudies showed that treatment of LLC-LN7 tumor cells with 1alpha,25-dih ydroxyvitamin D3 [1,25(OH)2D3] plus low dose gamma-interferon (IFN-gam ma) resulted in a synergistic reduction in tumor GM-CSF secretion and a blockage in the capacity of the tumor cells to induce GM-suppressor cells. The production of GM-CSF by bulk cultures of enzymatically diss ociated LLC-LN7 tumors that had been excised as s.c. tumors from mice was also blocked when the dissociated tumor was cultured with 1,25(OH) 2D3 plus IFN-gamma. Our previous and present studies showed that GM-su ppressor cells persist in bulk cultures of dissociated LLC-LN7 tumors after a 1-week period of culture. Addition of either 1,25(OH)2D3 or IF N-gamma did not diminish the persistence of GM-suppressor cells. Howev er, when tumor production of GM-CSF was inhibited by culture with both 1,25(OH)2D3 and IFN-gamma, the ability of the dissociated tumor cultu re to sustain the presence of GM-suppressor cells was blocked. This el imination of GM-suppressor cells by treatment of the dissociated tumor with 1,25(OH)2D3 and IFN-gamma coincided with increased expansion of CD8+ tumor-infiltrating leukocytes and increased cytotoxic T-lymphocyt es activity of tumor-infiltrating lymphocytes. These results suggest t hat blocking tumor production of GM-CSF can interrupt the suppressor-i nducing cascade of the tumor and enhance expansion and anti-tumor cyto lytic reactivity of tumor-infiltrating leukocytes.