Regression of engineered myeloma cells secreting interferon-gamma-inducing factor is mediated by both CD4(+)/CD8(+) T and natural killer cells.
IL-18 is a novel cytokine that stimulates T and NK cell activity and has potent antitumor effects. In this study, a mouse IL-18 gene was transfected into the mouse myeloma cell line J558. Our data demonstrated that (i) inoculation of 0.5x10(6) engineered tumor cells J558/IL-18 into syngeneic mice induced a Th1 dominant immune response and resulted in tumor regression in all 8/8 mice; (ii) the IL-18 antitumor effect was significantly decreased in mice depleted of either the CD4(+), or CD8(+), or NK cell subset, respectively but was completely abrogated in mice depleted of both CD4(+) and CD8(+) T cells; (iii) in vivo neutralization of IFN-gamma was accompanied by the growth of J558/IL-18 tumor in all the mice; and (iv) the J558/IL-18 tumor regression further induced protective immunity against a subsequent challenge by the parental J558 tumor, which is mediated by CD8(+) T cells as examined in the cytotoxicity assay in vitro and in the animal study in vivo. Taken together, our findings indicate that: (i) IL-18 can induce antitumor immune responses mediated by both CD4(+)/CD8(+) T cells and NK cells; and (ii) it is associated with IFN-gamma production. This study thus highlights the potential utility of IL-18 as an antitumor agent, a role that it can fulfil alone or in combination with other immunomodulatory cytokines such as IL-12.
Xiang
J
J
Departments of Microbiology and Pathology, Saskatoon Cancer Center, College of Medicine, University of Saskatchewan, 20 Campus Drive, Saskatoon, S7N 4H4, Saskatchewan, Canada. jxiang@scf.sk.ca
Chen
Z
Z
Huang
H
H
Moyana
T
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D007279:Injections, Subcutaneous; D020382:Interleukin-18 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D009365:Neoplasm Regression, Spontaneous; D014407:Tumor Cells, Cultured
D020382:Interleukin-18