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 shown to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) which induces the appearance of immunosuppressive granulocytic-macrophage progenitor cells (GM-suppressor cells). The present in vitro studies showed that treatment of LLC-LN7 tumor cells with 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] plus low dose gamma-interferon (IFN-gamma) 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 dissociated 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-suppressor 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 IFN-gamma did not diminish the persistence of GM-suppressor cells. However, 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 culture to sustain the presence of GM-suppressor cells was blocked. This elimination 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-lymphocytes activity of tumor-infiltrating lymphocytes. These results suggest that blocking tumor production of GM-CSF can interrupt the suppressor-inducing cascade of the tumor and enhance expansion and anti-tumor cytolytic reactivity of tumor-infiltrating leukocytes.
Young
M R
MR
Department of Veterans Affairs, Hines VA Hospital 60141.
Halpin
J
J
Wang
J
J
Wright
M A
MA
Matthews
J
J
Pak
A S
AS
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002117:Calcitriol