Dendritic cell activation by combined exposure to anti-CD40 plus interleukin (IL)-12 and IL-18 efficiently stimulates anti-tumor immunity

Abstract:  Despite as yet limited clinical effectiveness, dendritic cell (DC)-based immunotherapy remains a promising approach for the treatment of cancer, but requires further improvement in its immunostimulatory effectiveness. Potent anti-tumor immunity often depends on the induction of type 1 (T_H1) immune responses. Therefore, we combined different DC maturation stimuli that are known to induce T_H1 immunity [anti-CD40, interleukin (IL)-12, IL-18], with the aim to trigger a T_H1 driven anti-tumor CTL response. When compared with untreated DC or DC treated with anti-CD40 alone, DC matured with anti-CD40 plus IL-12 and IL-18 expressed significantly more IFN-γ and IL-12, induced enhanced CD8⁺ T-cell proliferation, prolonged synaptic interaction with T cells and increased CD8⁺ T-cell-mediated cytotoxicity. To analyse if these DC are able to induce efficient anti-tumor immunity, mice carrying a B16-OVA tumor were treated with tumor antigen (TA)-loaded DC that had been exposed to anti-CD40 or to anti-CD40 plus IL-12 and IL-18. Our data show that anti-CD40 plus IL-12 and IL-18 matured DC are superior to controls in retarding tumor growth. These data indicate that maturation of DC with anti-CD40 plus IL-12 and IL-18 potently stimulates the generation of an anti-tumor immune response and may lead to improved immunotherapeutic capacity of DC vaccination.