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In Vivo Interferon Regulatory Factor 3 Tumor Suppressor Activity in B16 Melanoma Tumors¹

Terry Fox Molecular Oncology Group, Lady Davis Institute-Jewish General Hospital [D. D., F. M., J. S., M. S., R. L., J. G., J. H.], and Departments of Microbiology and Immunology [D. D., J. H.], and Medicine [F. J., J. S., M. S., R. L., J. G., J. H.], McGill University, Montreal, Quebec H3T-1E2; School of Veterinary Medicine, Université de Montreal [D. M.], Montreal, Quebec H3C 3J7; and Center for Cell and Gene Therapy, Department of Pathology, McMaster University, Hamilton, Ontario L8N 3Z5 [J. B.], Canada

Delivery of transcription factors to cancer cells to reprogram gene expressionmay represent a novel strategy to augment the production of immunestimulatory cytokines and trigger a more potent antitumor response. In the present study, a bicistronic retroviral vector (AP2) was used to transduce B16-F0 melanoma cells with IFN regulatory factor (IRF)-3, which has been shown to activate type I IFN genes (IFN-ß and IFN-) as well as other cytokines. Gene-modified B16 melanoma cells were inoculated s.c. into C57BL/6 syngeneic mice. In animals receiving IRF-3 B16 melanoma cells, tumors grew at a 4- to 5-fold reduced rate, and tumors that developed from these mice had a moderate-to-dense infiltration of inflammatory cells, whereas only low levels of lymphocyte infiltration were observed in mock-transduced B16 tumors. Furthermore, tumor growth was not inhibited in severe-combined immunodeficient mice after inoculation of IRF-3-expressing B16 cells, which suggested that IRF-3-mediated antitumor responses were dependent on a functional adaptive lymphocyte response. Interestingly, these in vivo effects on tumor growth correlated with higher mRNA expression of chemokines such as MIP-1ß, RANTES, and IP-10, as well as dramatic increases in vitro in the inducibility of cytokine mRNA such as IFN-ß, TNF- and interleukin 6. Our results demonstrate that with weakly antigenic tumors such as B16 melanoma, IRF-3 gene transfer can mediate important antitumor responses. These findings suggest a novel role for IRF-3 as a potential molecular target for gene therapy of cancer.

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