Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4(+)25(+)Foxp3(+) Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation

Dendritic cells (DCs), the most potent antigen-presenting cells have been extensively applied in clinical trials for evaluation of antitumor immunity. However, the efficacy of DC-mediated cancer vaccines is still limited as they are unable to sufficiently break the immune tolerance. In this study, we constructed a recombinant adenoviral vector (AdV(IL-6)) expressing IL-6, and generated IL-6 transgene-engineered DC vaccine (DC(OVA/)(IL-6)) by transfection of murine bone marrow-derived ovalbumin (OVA)-pulsed DCs (DC(OVA)) with AdV(IL-6). We then assessed DC(OVA/)(IL-6)-stimulated cytotoxic T-lymphocyte (CTL) responses and antitumor immunity in OVA-specific animal tumor model. We demonstrate that DC(OVA/)(IL-6) vaccine up-regulates expression of DC maturation markers, secretes transgene-encoded IL-6, and more efficiently stimulates OVA-specific CTL responses and therapeutic immunity against OVA-expressing B16 melanoma BL6-10(OVA) in vivo than the control DC(OVA/Null) vaccine. Moreover, DC(OVA/)(IL-6)-stimulated CTL responses were relatively maintained in mice with transfer of CD4(+)25(+)Foxp3(+) Tr-cells, but significantly reduced when treated with anti-IL-6 antibody. In addition, we demonstrate that IL-6 down-regulates Foxp3-expression of CD4(+)25(+)Foxp3(+) Tr-cells in vitro. Taken together, our results demonstrate that AdV-mediated IL-6 transgene-engineered DC vaccine stimulates potent CTL responses and antitumor immunity by counteracting CD4(+)25(+) Tr immunosuppression via IL-6-induced Foxp3 down-regulation. Thus, IL-6 may be a good candidate for engineering DCs for cancer immunotherapy.