Dissimilar anti-tumour reactions induced by tumour cells engineered with the interleukin-2 or interleukin-15 gene in nude mice.
Interleukin (IL)-15 shares immuno-stimulatory properties with IL-2 and is a potent inducer of natural killer (NK) cell function. The major histocompatibility complex (MHC) class I-negative human small cell lung cancer (SCLC) cell line N592, engineered to express a modified IL-15 cDNA (N592/IL-15), secreted biologically active IL-15 (300-500 pg/ml), capable of boosting T-cell proliferation and NK activity 'in vitro'. The effect of IL-15 gene transfer on natural immunity 'in vivo' was assessed by xenotransplants in nude mice and compared with that of the IL-2 gene. N592 cells engineered with IL-2 (N592/IL-2) were promptly rejected, while N592/IL-15 displayed a significant delay in tumour growth and a slightly reduced take rate. However, in NK-depleted nude mice, N592/IL-15 displayed the same growth kinetics as unmodified N592 cells, and N592/IL-2 grew with slightly reduced kinetics. An impressive reactive cell infiltration, consisting mainly of macrophages and granulocytes, was associated with N592/IL-2 tumour rejection, while a more evident recruitment of NK cells was found in N592/IL-15 tumours. In both N592 transfected tumours, we found expression of chemoattractant molecules, such as granulocyte macrophage-colony stimulating factor (GM-CSF) and monocyte chemoattractant protein (MCP)-1, while macrophage inflammatory protein (MIP)-2 was produced by endothelial cells only in N592/IL-2 tumours. In this tumour, very few and severely damaged microvessels were found, while microvessels were numerous in N592/IL-15 tumours. The potent recruitment of NK cells mediated by IL-15 gene transfer suggests its possible therapeutic use in tumours lacking MHC class I.
Di Carlo
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Dipartimento di Oncologia e Neuroscienze, Università di Chieti, Italy.
Meazza
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R
Basso
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Rosso
O
O
Comes
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A
Gaggero
A
A
Musiani
P
P
Santi
L
L
Ferrini
S
S
D000818:Animals; D018288:Carcinoma, Small Cell / Q000235:genetics; D018932:Chemokine CCL2 / Q000032:analysis; D005260:Female; D018014:Gene Transfer Techniques; D005805:Genes, MHC Class I / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D019409:Interleukin-15 / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics; D019402:Macrophage Inflammatory Proteins / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured
D018932:Chemokine CCL2; D019409:Interleukin-15; D007376:Interleukin-2; D019402:Macrophage Inflammatory Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor