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

The glycolipid α‐galactosylceramide (α‐GalCer), ligand of NKT cells, has been recently shown to induce antitumor immunity in mice through the induction of IL‐12 production by dendriticcells. In the present study we compared α‐GalCer and rIL‐12 antitumor activities in the treatment of hepatic metastases of the C‐26 murine colon carcinoma. We show that in immunocompetent mice the two molecules display similar efficacy, whereas in mice knockout (KO) for β2‐microglobulin (β2m), IFN‐γ or IL‐12p40, α‐GalCer antitumor activity is severely impaired. Conversely,in all such KO mice, rIL‐12 retains its efficacy. In this context, the IL‐12 effect relies on NK cell function since it is abrogated by antibodies to NK1.1, expressed by both NK and NKT cells, but not in β2m KO mice that lack NKT and CD8 T cells, but have a perfectly functional NK cell population. Furthermore, in IFN‐γ and IL‐12p40 double KO mice, exogenous rIL‐12 completely loses antitumor efficacy, suggesting the existence of an IFN‐γ‐independent IL‐12 effect that does require the presence of endogenous IL‐12p40 chain.