NK and CD8+ T cell‐mediated eradication of poorly immunogenic B16‐F10 melanoma by the combined action of IL‐12 gene therapy and 4‐1BB costimulation

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Abstract
In previous reports, systemic administration of a stimulatory monoclonal antibody directed against the 4‐1BB receptor had no effect on survival or tumor burden in mice inoculated with the poorly immunogenic B16‐F10 melanoma. We combined IL‐12 gene transfer with 4‐1BB costimulation to explore a previously noted cooperative anti‐tumor effect against this model tumor. We hypothesize that the innate immune response mediated by IL‐12‐activated natural killer (NK) cells initiates the activation of the immune system, leading to the priming of T cells, whereas 4‐1BB costimulation enhances the function of primed tumor‐specific T cells. The effect of the combination therapy on the growth of subcutaneous (s.c.) tumors and pulmonary metastasis was examined. The combination therapy significantly retarded the growth of subcutaneously‐inoculated tumors, and 50% of tumor‐bearing mice survived with complete tumor regression. In contrast, neither IL‐12 gene transfer nor anti‐4‐1BB antibody administration alone was as effective. Enhanced CTL activity against both B16‐F10 tumor cells and TRP‐2‐pulsed EL4 syngeneic tumor cells was observed in tumor‐bearing animals treated with the combination therapy 2 weeks after treatment and, in long‐term survivors from this combination therapy, at >120 days. In a pulmonary metastatic model, only the combination therapy generated significant protection against metastasis. In vivo depletion of NK or CD8+ but not CD4+ subsets eliminated the protective immunity. Furthermore, NK cell depletion significantly reduced both tumor‐specific CTL activity and the number of tumor‐specific IFN‐γ‐producing cells, suggesting that this synergistic effect requires the participation of both NK and CD8+ T cells.