Synergistic action of fms-like tyrosine kinase 3 ligand and CD40 ligand inthe induction of dendritic cells and generation of antitumor immunity in vivo

Daily treatment of mice with fms-like tyrosine kinase 3 ligand (Flt3L) lead s to a significant increase in the number of dendritic cells and induces an titumor immunity. Here, we show that Flt3L and CD40 ligand (CD40L) synergiz e in the generation of immune responses against two poorly immunogenic tumo rs, leading to complete tumor rejection in a high proportion of mice. Recha llenge of the Flt3L + CD40L-treated mice with the immunizing tumor resulted in complete inhibition of tumor growth, indicating that these animals had developed long-lasting antitumor immunity. In addition, we demonstrate that endogenous CD40L plays a critical role in antitumor immunity, since blocka de of CD40-CD40L interactions in vivo prevents the generation of antitumor immunity in therapeutic and vaccination protocols. Dendritic cells generate d in mice treated with Flt3L alone or in combination with CD40L were equall y potent in stimulating allogeneic T cells and expressed similar levels of MHC class II, CD80, and CD86. However, mice treated with Flt3L + CD40L had significantly more dendritic cells than mice treated with either of the cyt okines alone, suggesting that CD40L promotes the proliferation and/or survi val of dendritic cells generated by Flt3L treatment, Dendritic cells genera ted in this manner are likely to be involved in the priming of antitumor im mune responses.