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.