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,
*
Dipartimento di Oncologia e Neuroscienze, Università di Chieti, Chieti, Italy;
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy;
Dipartimento di Oncologia Clinica e Sperimentale, Università di Genova, Genova, Italy; and
§
Institute of Medical Virology University of Zurich, Zurich, Switzerland
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-1ß, TNF-
, and
IFN-
, 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.
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