The combined action of IL-15 and IL-12 gene transfer can induce tumor cell rejection without T and NK cell involvement.
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.
Di Carlo
E
E
Dipartimento di Oncologia e Neuroscienze, Università di Chieti, Chieti, Italy.
Comes
A
A
Basso
S
S
De Ambrosis
A
A
Meazza
R
R
Musiani
P
P
Moelling
K
K
Albini
A
A
Ferrini
S
S
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018288:Carcinoma, Small Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D019409:Interleukin-15 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D007970:Leukopenia / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection / Q000276:immunology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D019409:Interleukin-15; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor