Enhancement of antitumor activity by a genetically-modified dendritic cell vaccine expressing Interleukin-15 and its receptor

Dendritic cells (DCs) are powerful antigen presenting cells that are capable of activating and directing naive T and B cells. This has lead to their study as potential anticancer vaccines. Tumor cells; however, have correspondingly developed a number of mechanisms to evade the immune response by suppressing DC function and reducing the effectiveness of DC antitumor vaccination. The ability of tumor cells to suppress DC function may be overcome by the cytokine interleukin-15 (IL-15). IL-15 has also been shown to induce T-cell proliferation, enhance cytolytic effector cells including natural killer (NK) and cytotoxic T-cells, and enhance stimulation of B-cells. IL-15 functions through interaction with its receptor (IL-15Ra) that presents IL-15 in trans to immune effectors cells. The efficacy of exogenously administered IL-15 may be limited by the availability of IL-15Ra. BALB-neuT transgenic mice develop breast cancers as a consequence of mammary gland-specific expression of an activated neu oncogene. We examined the antitumor effect of adenoviral-mediated gene transfer of the combination of IL-15 and IL-15Ra to augment a DC vaccine directed against the neu oncoprotein in these mice. Methods: Bone marrow-derived DCs were generated from BALB/c mice and transduced with recombinant adenoviruses expressing a non-signaling truncated neu antigen, murine IL-15 and/or its receptor, IL-15Ra. BALB-neuT mice at 10-12 weeks of age were subcutaneously vaccinated with four weekly injections of 1 × 106 DCs and followed for tumor development and immune response. Results: Mice vaccinated with DCs expressing the neu antigen, IL-15 and IL-15Ra had significantly delayed onset of mammary carcinomas with 70% of animals tumor free at 25 weeks compared to none of the unvaccinated control mice, 10% of animals treated with DC expressing the neu antigen, 30% of animals vaccinated with DCs expressing neu + IL-15, and 40% of animals vaccinated with DC expressing neu + IL-15Ra. Animals vaccinated with DCs expressing the neu antigen, IL-15 and IL-15Ra exhibited significantly greater antibody responses to the neu antigen compared to those treated with DCs expressing neu alone, or in combination with IL-15, or IL-15Ra. Sera from vaccinated mice exhibited antibody-dependant cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) against neu-expressing target cells and induced down-regulation of neu signaling in vitro. Conclusion: Antitumor vaccination with genetically-modified DCs expressing the neu antigen, IL-15 and IL-15Ra increased tumor-free survival highlighting the potential for the use of IL-15 and IL-15Ra gene transfer to augment DC anticancer vaccines.