Antitumor effects on mouse melanoma elicited by local secretion of interleukin-12 and their enhancement by treatment with interleukin-18.
To investigate the mechanism of the antitumor effect of locally secreted interleukin-12 (IL-12), we introduced the IL-12 p35 and p40 cDNAs into mouse B16 melanoma cells. IL-12 gene-transfected B16 melanoma (B16/IL12) showed marked retardation of tumor growth when implanted subcutaneously into syngeneic mice. In these mice, depletion of not only Natural Killer (NK) cells but also CD8+ T cells diminished the antitumor effect of locally secreted IL-12. Immunohistochemical analysis showed that NK cells and macrophages accumulated more densely at the center and periphery of B16/IL12 tumors than that of parental B16 tumors, whereas CD4+ T cells and CD8+ T cells accumulated sparsely only at the periphery of both transfected and untransfected tumors. Systemic treatment with interleukin-18 (IL-18) markedly inhibited the growth of B16/IL12 but did not influence the tumor growth of parental B16 cells in vivo. These results suggest that local IL-12 secretion can retard the growth of B16 melanoma mediated primarily by NK cells and indirectly by CD8+ T cells and that its antitumor effect is augmented by systemic treatment with the novel cytokine IL-18.
Nagai
H
H
Department of Dermatology, Kobe University School of Medicine, Japan.
Hara
I
I
Horikawa
T
T
Fujii
M
M
Kurimoto
M
M
Kamidono
S
S
Ichihashi
M
M
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D004195:Disease Models, Animal; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology*; D051379:Mice; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology*; D014407:Tumor Cells, Cultured
D020382:Interleukin-18; D018664:Interleukin-12