Abstract
The cooperative antitumor effects of IL-12 and IL-15 gene transfer were studied in the N592 MHC class I-negative small cell lung cancer cell line xenotransplanted in nude mice. N592 cells engineered to secrete IL-15 displayed a significantly reduced tumor growth kinetics, and a slightly reduced tumor take rate, while N592 engineered with IL-12 displayed only minor changes in their growth in nude mice. However, N592 cells producing both cytokines were completely rejected, and produced a potent local bystander effect, inducing rejection of coinjected wild-type tumor cells. N592/IL-12/IL-15 cells were completely and promptly rejected also in NK-depleted nude mice, while in granulocyte-depleted animals a slight delay in the rejection process was observed. Immunohistochemical analyses of the N592/IL-12/IL-15 tumor area in intact nude mice revealed the presence of infiltrating macrophages, granulocytes, and NK cells, and expression of inducible NO synthase and of secondary cytokines such as IL-1beta, TNF-alpha, and IFN-gamma, and at higher levels GM-CSF, macrophage-inflammatory protein-2, and monocyte chemoattractant protein-1. In NK cell-depleted nude mice, numerous macrophages and granulocytes infiltrated the tumor, and a strong expression of macrophage-inflammatory protein-2 and inducible NO synthase was also observed. Finally, macrophages cocultured with N592/IL-12/IL-15 produced NO in vitro, and inhibited tumor cell growth, further suggesting their role as effector cells in this model.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adjuvants, Immunologic / genetics
-
Adjuvants, Immunologic / metabolism
-
Animals
-
Carcinoma, Small Cell / immunology
-
Carcinoma, Small Cell / metabolism
-
Carcinoma, Small Cell / pathology
-
Carcinoma, Small Cell / prevention & control*
-
Cell Division / genetics
-
Cell Division / immunology
-
Coculture Techniques
-
Cytotoxicity, Immunologic
-
Drug Synergism
-
Female
-
Gene Expression Regulation / immunology
-
Gene Transfer Techniques*
-
Graft Rejection / genetics
-
Graft Rejection / immunology*
-
Graft Rejection / pathology
-
Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
-
Granulocytes / immunology
-
Granulocytes / metabolism
-
Humans
-
Immunohistochemistry
-
Interferon-gamma / metabolism
-
Interleukin-12 / biosynthesis
-
Interleukin-12 / genetics*
-
Interleukin-12 / metabolism
-
Interleukin-15 / biosynthesis
-
Interleukin-15 / genetics*
-
Interleukin-15 / metabolism
-
Killer Cells, Natural / immunology*
-
Leukopenia / immunology
-
Lung Neoplasms / immunology
-
Lung Neoplasms / metabolism
-
Lung Neoplasms / pathology
-
Lung Neoplasms / prevention & control*
-
Lymphocyte Depletion
-
Macrophages / immunology
-
Macrophages / metabolism
-
Mice
-
Mice, Nude
-
Neoplasm Transplantation
-
Nitric Oxide / biosynthesis
-
Spleen / cytology
-
Spleen / immunology
-
Spleen / metabolism
-
T-Lymphocytes / immunology*
-
Transfection / immunology
-
Transplantation, Heterologous
-
Tumor Cells, Cultured
Substances
-
Adjuvants, Immunologic
-
Interleukin-15
-
Interleukin-12
-
Nitric Oxide
-
Interferon-gamma
-
Granulocyte-Macrophage Colony-Stimulating Factor