Interleukin-15 and Its Receptor Augment Dendritic Cell Vaccination against theneuOncogene through the Induction of Antibodies Partially Independent of CD4 Help

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Abstract
Interleukin-15 (IL-15) stimulates the diffrentiation and proliferation of T, B, and natural killer cells; enhances CD8+ cytolytic T-ceII activity; helps maintain CD44hiCD8+ memory T cells; and stimulates immunoglobulin synthesis by B cells. IL-15 is trans-presented to effector cells by its receptor, IL-15Rα, expressed on dendritic cells (DC) and monocytes. We examined the antitumor effect of adenoviral-mediated gene transfer of IL-15 and IL-15Rα to augment a DC vaccine directed against the NEU (ErbB2) oncoprotein. Transgenic BALB-neuT mice vaccinated in late-stage tumor development with a DC vaccine expressing a truncated NEU antigen, IL-I5, and its receptor (DCAd.Neu+Ad_mIL-15+Ad.mlL-15Rα) were protected from mammary carcinomas, with 70% of animals tumor-free at 30 weeks compared with none of the animals vaccinated with NEU alone (DCAd.Neu). The combination of neu, IL-15, and IL-15Rα gene transfer leads to a significaintly greater anti-NEU antibody response compared with mice treated with DCAd.Neu or DCAd.Neu combined with either IL-15 (DCAd.Neu+Ad.mlL-15) or lL-15Rα (DCAd.Neu+Ad.mlL-15Rα). The antitumor effect was antibody mediated and involved modulation of NEU expression and signaIing. Depletion of CD4+ cells did not abrogate the antitumor effect of the vaccine, nor did it inhibit the induction of anti-NEU aritibodies. Coexpression of IL-15 and IL-15Rα in an anticancer vaccine enhanced immune responses against the NEU antigen and may overcome impaired CD4+ T-helper function. Cancer Res; 70(3); 1072–81