Interleukin-15 and its receptor augment dendritic cell vaccination against the neu oncogene through the induction of antibodies partially independent of CD4 help.
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.
Steel
Jason C
JC
Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1374, USA.
Ramlogan
Charmaine A
CA
Yu
Ping
P
Sakai
Yoshio
Y
Forni
Guido
G
Waldmann
Thomas A
TA
Morris
John C
JC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000235:genetics / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D053647:Receptors, Interleukin-15 / Q000235:genetics / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic
D015704:CD4 Antigens; D019409:Interleukin-15; D018719:Erb-b2 Receptor Tyrosine Kinases; D053647:Receptors, Interleukin-15