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 CD44(hi)CD8(+) memory T cells; and stimulates immunoglobulin synthesis by B cells. IL-15 is trans-presented to effector cells by its receptor, IL-15Ralpha, expressed on dendritic cells (DC) and monocytes. We examined the antitumor effect of adenoviral-mediated gene transfer of IL-15 and IL-15Ralpha 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 (DC(Ad.Neu+Ad_mIL-15+Ad.mlL-15Ralpha)) were protected from mammary carcinomas, with 70% of animals tumor-free at 30 weeks compared with none of the animals vaccinated with NEU alone (DC(Ad.Neu)). The combination of neu, IL-15, and IL-15Ralpha gene transfer leads to a significaintly greater anti-NEU antibody response compared with mice treated with DC(Ad.Neu) or DC(Ad.Neu) combined with either IL-15 (DC(Ad.Neu+Ad.mlL-15)) or lL-15Ralpha (DC(Ad.Neu+Ad.mlL-15Ralpha)). 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-15Ralpha in an anticancer vaccine enhanced immune responses against the NEU antigen and may overcome impaired CD4(+) T-helper function.