Dendritic cells in models of tumor immunity. Role of Flt3 ligand.

Cancer immunotherapy might be based on the administration to cancer patients of dendritic cells (DC) 'pulsed' with tumor-specific antigens. An alternative approach is to directly expand and/or activate DC in vivo using the cytokine Flt3 Ligand (FL). In mice, FL can drive large expansion of both lymphoid-related DC that appears to selectively enhance Th1-like immune responses and myeloid-related DC that enhances a more mixed Th phenotype. Immunization of FL-treated mice with a protein antigen leads to increased production of antibodies specific for that protein as well as to antigen-specific helper T cell responses. Studies of mouse tumor models have demonstrated that FL administration leads to the generation of protective anti-tumor immune responses, these effects being mediated by CTL and/or NK cells. When, FL has only minor or short term effects, the anti-tumor response can be significantly amplified by adding other cytokines, known to act at the T cell level, such as CD40 ligand (CD40L) or 4-1BBL, a TNF family member. Thus, combination of FL + CD40L or FL + 4-1BBL have superior anti-tumor effects vs. either cytokine alone. In conclusion, cytokines offer a variety of novel approaches for the treatment of cancer, infectious or auto-immune diseases.