Interleukin-12 gene therapy of a weakly immunogenic mouse mammary carcinoma results in reduction of spontaneous lung metastases via a T-cell-independent mechanism
Al. Rakhmilevich et al., Interleukin-12 gene therapy of a weakly immunogenic mouse mammary carcinoma results in reduction of spontaneous lung metastases via a T-cell-independent mechanism, CANC GENE T, 7(6), 2000, pp. 826-838
In our previous studies using gene gun-mediated delivery of interleukin 12
(IL-12) cDNA in vivo, we observed T-cell-mediated regression of established
murine tumors and demonstrated the induction of systemic immunity in test
animals. In this study, we further characterized the antitumoral and anti-m
etastatic effect of this gene therapy approach by employing two murine meta
static mammary tumor models: the immunogenic TS/A adenocarcinoma and the we
akly immunogenic 4T1 adenocarcinoma. In the TS/A model, gene transfer into
the skin overlying an established intradermal tumor with an IL-12 cDNA expr
ession vector resulted in complete tumor regression in 50% of mice followed
by the development of immunological memory. In contrast, the growth of the
intradermal 4T1 tumors was not affected by the IL-12 gene therapy protocol
. However, this treatment resulted in a substantial reduction of spontaneou
s metastases in the lungs of 4T1 tumor-bearing mice and significantly prolo
nged their survival time. T cells were not required for this anti-metastati
c effect, because it was also observed in nude mice and in mice depleted of
CD4(+) and CD8(+) T cells. Tumor-draining lymph node cells obtained from 4
T1 tumor-bearing mice treated with IL-12 cDNA exhibited increased natural k
iller (NK) activity and produced enhanced levels of interferon-gamma (IFN-g
amma) compared with similar mice treated with luciferase cDNA. In addition,
in vivo depletion of NK cells or neutralization of IFN-gamma resulted in p
artial suppression of the anti-metastatic effect of IL-12 gene therapy, sug
gesting the involvement of both NK cells and IFN-gamma in this effect.