Interleukin-18 and the costimulatory molecule B7-1 have a synergistic anti-tumor effect on murine melanoma; implication of combined immunotherapy for poorly immunogenic malignancy.
Interleukin-18 has been described recently as a cytokine secreted primarily by Kupffer cells. Furthermore, it has been shown that it has significant anti-tumor effects, which are mediated by T cells and natural killer cells, in a manner similar to interleukin-12. Here, we report the evaluation of the effects of the systemic administration of interleukin-18 in combination with B7-1 (CD80) expressed on tumor cells [interleukin-18 + B7-1] on the growth of murine B16 melanoma in vivo. After the subcutaneous inoculation of B16 melanoma, B16 tumors grew progressively in immunocompetent syngeneic C57BL/6 mice. Mice treated with either interleukin-18 or immunized with B7-1-transduced B16 did not demonstrate significant anti-tumor effect. The combination of the two treatments, however, resulted in dramatic suppression of melanoma formation, tumor growth, and a significant improvement in survival. Inhibitory effects of [interleukin-18 + B7-1] on lung metastasis in mice were also detected. Additionally, mice treated with [interleukin-18 + B7-1] showed an increase of natural killer cytotoxicity and interferon-gamma production in vivo. Unlike [interleukin-18 + B7-1], [interleukin-12 + B7-1] did not have a strong anti-tumor effect against B16 melanoma. Histologic characterization after the [interleukin-18 + B7-1] treatment confirmed the infiltration of natural killer cells into the tumor, suggesting that natural killer cells may be involved in the [interleukin-18 + B7-1]-induced anti-tumor effect. This finding was confirmed by showing that depletion of NK1.1+ cells before immunization inhibits the [interleukin-18 + B7-1]-induced anti-tumor effect. Depletion of CD3+ cells in vivo also decreased the anti-tumor effect of [interleukin-18 + B7-1], suggesting the importance of CD3+ T cells. Collectively, combination with interleukin-18 and B7-1 expression has synergistic anti-tumor effects against B16 murine melanoma.
Cho
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Department of Dermatology, Department of Microbiology/Immunology, College of Medicine, The Catholic University of Korea.
Kim
T G
TG
Lee
W
W
Hwang
Y I
YI
Cho
H I
HI
Han
H
H
Kwon
O
O
Kim
D
D
Park
H
H
Houh
D
D
D000818:Animals; D000941:Antigens / Q000032:analysis; D000950:Antigens, Ly; D000954:Antigens, Surface; D018122:B7-1 Antigen / Q000008:administration & dosage*; D017252:CD3 Complex / Q000032:analysis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D020382:Interleukin-18 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D037181:Lectins, C-Type; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000032:analysis
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D018122:B7-1 Antigen; D017252:CD3 Complex; D020382:Interleukin-18; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins