Local secretion of IL-12 augments the therapeutic impact of dendritic cell-tumor cell fusion vaccination.
BACKGROUND: The development of dendritic cell (DC)-tumor fusion vaccines is a promising approach in cancer immunotherapy. Using fusion vaccines allows a broad spectrum of known and unidentified tumor-associated antigens to be presented in the context of MHC class I and class II molecules, with potent co-stimulation provided by the DCs. Although DC-tumor fusion cells are immunogenic, murine studies have shown that effective immunotherapy requires a third signal, which can be provided by exogenous interleukin 12 (IL-12). Unfortunately, systemic administration of IL-12 induces severe toxicity in cancer patients, potentially precluding clinical use of this cytokine to augment fusion vaccine efficacy. To overcome this limitation, we developed a novel approach in which DC-tumor fusion cells locally secrete IL-12, then evaluated the effectiveness of this approach in a murine B16 melanoma model. MATERIALS AND METHODS: Tumor cells were stably transduced to secrete murine IL-12p70. These tumor cells were then electrofused to DC to form DC-tumor heterokaryons. These cells were used to treat established B16 pulmonary metastases. Enumeration of these metastases was performed and compared between experimental groups using Wilcoxon rank sum test. Interferon γ enzyme-linked immunosorbent spot assay was performed on splenocytes from treated mice. RESULTS: We show that vaccination with DCs fused to syngeneic melanoma cells that stably express murine IL-12p70 significantly reduces counts of established lung metastases in treated animals when compared with DC-tumor alone (P = 0.029). Interferon γ enzyme-linked immunosorbent spot assays suggest that this antitumor response is mediated by CD4(+) T cells, in the absence of a tumor-specific CD8(+) T cell response, and that the concomitant induction of antitumor CD4(+) and CD8(+) T cell responses required exogenous IL-12. CONCLUSIONS: This study is, to the best of our knowledge, the first report that investigates the impact of local secretion of IL-12 on antitumor immunity induced by a DC-tumor fusion cell vaccine in a melanoma model and may aid the rational design of future clinical trials.
Tan, C; Dannull, J; Nair, SK; Ding, E; Tyler, DS; Pruitt, SK; Lee, WT
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