Transfection of macrophage inflammatory protein 1 alpha into B16 F10 melanoma cells inhibits growth of pulmonary metastases but not subcutaneous tumors.
Macrophage inflammatory protein 1 alpha (MIP-1 alpha), a CC chemokine, is a chemoattractant for T cells and immature dendritic cells. Plasmacytoma cells expressing MIP-1 alpha generate a cytotoxic T cell response without affecting tumor growth. To understand this discrepancy, we compared a local tumor model with a metastatic one using MIP-1 alpha-transfected B16 F10 melanoma cells. Clonal idiosyncrasies were controlled by selecting three lipotransfected tumor clones and two pcDNA vector transfected control clones with equivalent in vitro proliferative capacities. No significant differences were seen between the MIP-1 alpha-producing and control melanoma cells after s.c. injection in the hind leg. All animals had a leg diameter of 10 cm in 18.5-21.5 days. However, after i.v. injection the number of pulmonary foci was significantly reduced in the MIP-1 alpha-producing clones. Injection of 10(6) control transfected cells resulted in a median of 98.5 tumor foci in 2 wk, whereas the injection of the MIP-1 alpha-producing clones resulted in 89.5, 26.5, and 0 foci. The number of metastatic foci was inversely proportional to the amount of MIP-1 alpha produced by the clone in vitro. Flow cytometry showed a significant increase in CD8(+) cells in lungs of mice with MIP-1 alpha-transfected tumors 3 days after injection. This increase was not maintained 10 days later despite continued production of MIP-1 alpha. The protection offered by transfection with MIP-1 alpha was significantly impaired in beta(2)-microglobulin(-/-) mice. Our findings suggest that MIP-1 alpha is effective in preventing the initiation of metastasis, but not at sustaining an effective antitumor response.
van Deventer
Hendrik W
HW
Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. hvand@med.unc.edu
Serody
Jonathon S
JS
McKinnon
Karen P
KP
Clements
Casey
C
Brickey
W June
WJ
Ting
Jenny P-Y
JP
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002455:Cell Division; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D005260:Female; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012878:Skin Neoplasms / Q000517:prevention & control*; D014162:Transfection
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins