Introduction of genes encoding immuno-stimulatory
cytokines into
cancer cells is known to enhance antitumor immunity.
CD40 ligand (
CD40L, CD154) and
fms-like tyrosine kinase 3 ligand (Flt3L) are recently identified
cytokines, which have been demonstrated to stimulate antitumor immunity in several
cancer models. However little is known about antitumor activity of Ftl3L and
CD40L against
hepatocellular carcinoma (HCC). In the present study, we constructed replication-defective adenoviruses expressing Flt3L and
CD40L and examined their therapeutic efficacy on mouse HCC, MH134 cells.
Subcutaneous injection of MH134 cells genetically engineered to express Flt3L and/or
CD40L developed
tumors in all the syngeneic immunocompetent mice, but
tumor growth was significantly delayed as compared to control mice. Partial inhibition of this antitumor effect in athymic nude mice suggests that both innate and adaptive immunity appear to play a role. It was shown by immunodepletion of NK cells with anti-asialo-GM1 antibody that the effector cells involved in innate immunity are NK cells. In a therapeutic setting, however, injection of adenovirus expressing Flt3L or
CD40L into pre-established MH134
tumors exhibited no efficacy. These data demonstrate that Flt3L and
CD40L induce significant, but only weak, antitumor immunity against MH134 cells presumably through both innate and adaptive immunity. Our results suggest that immuno-gene therapy with Flt3L and
CD40L may need adjuvant modalities to achieve strong immune response.