1 alpha,25-dihydroxyvitamin D3 plus gamma-interferon blocks lung tumor production of granulocyte-macrophage colony-stimulating factor and induction of immunosuppressor cells.

Abstract

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.

• Authors: M R Young, J Halpin, J Wang, M A Wright, J Matthews, A S Pak
• Journal: Cancer research (Cancer Res) Vol. 53 Issue 24 Pg. 6006-10 (Dec 15 1993) ISSN: 0008-5472 [Print] United States
• PMID: 8261414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Interferon-gamma
• Granulocyte-Macrophage Colony-Stimulating Factor
• Calcitriol

Topics

• Animals
• Calcitriol (pharmacology)
• Cells, Cultured
• Cytotoxicity, Immunologic
• Granulocyte-Macrophage Colony-Stimulating Factor (biosynthesis)
• Interferon-gamma (pharmacology)
• Lung Neoplasms (metabolism)
• Mice
• Mice, Inbred C57BL
• T-Lymphocytes, Regulatory (physiology)