The Combined Action of IL-15 and IL-12 Gene Transfer Can Induce Tumor Cell Rejection Without T and NK Cell Involvement

• Published in: The Journal of immunology (1950) Vol. 165; no. 6; pp. 3111 - 3118
• Main Authors: Di Carlo, Emma, Comes, Alberto, Basso, Stefania, De Ambrosis, Alessandro, Meazza, Raffaella, Musiani, Piero, Moelling, Karin, Albini, Adriana, Ferrini, Silvano
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.09.2000
• Subjects: 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.6.3111

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.