Interleukin-2 gene transfer potentiates the α-galactosylceramide-stimulated antitumor effect by the induction of TRAIL in NKT and NK cells in mouse models of subcutaneous and metastatic carcinoma

Abstract

α-Galactosylceramide (α-GalCer) is a potent CD1d ligand that activates natural

killer like T (NKT) cells, leading to the production of helper T (Th) 1 and Th2

cytokines that mediate various immunemodulatory and antitumor effects. Here,

we determined whether the administration of adenovirus-vector-encoding mouse

interleukin-2 (AdmIL-2) can augment the antitumor effect of α-GalCer on

subcutaneous and metastatic tumors in mice. Mice were intraperitoneally injected

with α-GalCer on days 7, 10, and 13 after tumor inoculation, with or without

intratumoral injection of AdmIL-2 on day 7. α-GalCer treatment increased the

serum levels of interferon-γ, while intratumoral injection of AdmIL-2 elevated

serum IL-2 levels. A combination of α-GalCer and AdmIL-2 (α-GalCer/AdmIL-2)

inhibited the in vivo tumor growth and improved the survival of tumor-bearing

mice, as compared to the use of a single agent. Experiments on spontaneous

metastasis models revealed that α-GalCer/AdmIL-2 reduced lung metastasis and

prolonged survival, as compared to control groups. In addition, the splenic and

liver mononuclear cells from mice treated with α-GalCer/AdmIL-2 showed

enhanced cytolytic activity against NK-sensitive YAC-1 and NK-resistant 3LL

tumors. Moreover, α-GalCer/AdmIL-2 treatment expanded the absolute numbers

of lung and liver NK, NKT, and T cells as well as the TNF-related

apoptosis-inducing ligand (TRAIL) expression of these cells. This study shows

the efficacy of α-GalCer/AdmIL-2 immunomodulatory therapy, and provides a

cellular mechanism on how it exerts the antitumor effects.