Different requirements for alpha-galactosylceramide and recombinant IL-12 antitumor activity in the treatment of C-26 colon carcinoma hepatic metastases

The glycolipid a-galactosylceramide (alpha -GalCer), ligand of NKT cells, h as been recently shown to induce antitumor immunity in mice through the ind uction of IL-12 production by dendritic cells. In the present study we comp ared alpha -GalCer and rIL-12 antitumor activities in the treatment of hepa tic metastases of the C-26 murine colon carcinoma. We show that in immunoco mpetent mice the two molecules display similar efficacy, whereas in mice kn ockout (KO) for beta2-microglobulin (beta 2m), IFN-gamma or IL-12p40, alpha -GalCer antitumor activity is severely impaired. Conversely, in all such K O mice, rIL-12 retains its efficacy. In this context, the IL-12 effect reli es on NK cell function since it is abrogated by antibodies to NK1.1, expres sed by both INK and NKT cells, but not in beta 2m KO mice that lack NKT and CD8T cells, but have a perfectly functional NK cell population. Furthermor e, in IFN-gamma and IL-l2p4O double KO mice, exogenous rIL-12 completely lo ses antitumor efficacy, suggesting the existence of an IFN-gamma -independe nt IL-12 effect that does require the presence of endogenous IL-12p40 chain .