Upregulation of natural killer cells functions underlies the efficacy of intratumorally injected dendritic cells engineered to produce interleukin-12.
OBJECTIVE
Injection of dendritic cells (DC) engineered with recombinant adenoviral vectors to produce interleukin-12 (IL-12) inside experimental murine tumors frequently achieves complete regressions. In such a system the function of CD8(+) T cells has been shown to be an absolute requirement, in contrast to observations made upon depletion of CD4(+) T cells, which minimally affected the outcome. The aim of this work was to study the possible involvement of natural killer (NK) cells in this setting.


RESULTS
Depletions with anti-AsialoGM1 antiserum showed only a small decrease in the proportion of complete regressions obtained that correlated with induction of NK activities in lymphatic tissues into which DC migrate, whereas combined depletions of CD4(+) and NK cells completely eliminated the antitumor effects. Likewise in vivo neutralization of interferon-gamma (IFN-gamma) also eliminated those therapeutic effects. Trying to define the cellular role played by NK cells in vivo, it was observed that injection of cultured DC inside the spleen of T- and B-cell-deficient (Rag1(-/-)) mice induced upregulation of NK activity only if DC had been adenovirally engineered to produce IL-12. In addition, identically transfected fibroblasts also activated NK cells, indicating that IL-12 transfection was the unique requirement. Equivalent human DC only activated in vitro the cytolytic and cytokine-secreting functions of autologous NK cells if transfected to express human IL-12.


CONCLUSIONS
Overall, these results point out an important role played by NK cell activation in the potent immunotherapeutic effects elicited by intratumoral injection of IL-12--secreting DC and that NK activation under these conditions is mainly, if not only, dependent on IL-12.
Rodríguez-Calvillo
Mercedes
M
Gene Therapy Unit, Department of Internal Medicine, University of Navarra, Pamplona, Spain.
Duarte
Marina
M
Tirapu
Iñigo
I
Berraondo
Pedro
P
Mazzolini
Guillermo
G
Qian
Chen
C
Prieto
Jesús
J
Melero
Ignacio
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015704:CD4 Antigens / Q000032:analysis; D002469:Cell Separation; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D005677:G(M1) Ganglioside / Q000032:analysis; D005818:Genetic Engineering; D006028:Glycosphingolipids / Q000032:analysis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008280:Magnetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D014162:Transfection
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D005456:Fluorescent Dyes; D006028:Glycosphingolipids; D018664:Interleukin-12; D015847:Interleukin-4; D005677:G(M1) Ganglioside; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016650:Fluorescein-5-isothiocyanate