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Tumor-infiltrating Macrophages Are Involved in Suppressing Growth and Metastasis of Human Prostate Cancer Cells by INF-ß Gene Therapy in Nude Mice¹

Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Purpose: This study was to determine the role of tumor-infiltrating macrophages in IFN-ß-induced host defense against prostate cancer.

Experimental Design: Efficacy of adenovirus-mediated IFN-ß gene therapy against orthotopic xenografts of human prostate cancer was tested in macrophage-compromised nude mice. Immunohistochemistry and Northern blotting were used to elucidate mechanisms responsible for the IFN-ß gene therapy.

Results: PC-3MM2 human prostate cancer cells were inoculated into the prostates of nude mice. Intralesional injection of an adenoviral vector-encoding murine IFN-ß (AdmIFN-ß) but not control vector AdE/1 suppressed growth of PC-3MM2 tumors in a dose-dependent manner, with a maximal reduction of tumor weight by 85% at 2 x 10⁹ plaque-forming units. The therapy prevented metastasis, eradicated established metastases in some mice, and prolonged the survival of tumor-bearing mice. The efficacy of AdmIFN-ß therapy was reduced significantly in mice treated with macrophage-selective anti-Mac-1 and anti-Mac-2 antibodies. Moreover, the i.p. injection of the antibodies restored the tumorigenicity of PC-3MM2 cells stably engineered with murine IFN-ß gene. Tumor-infiltrating macrophages, significantly increased in AdmIFN-ß-injected lesions, were depleted by the antibodies. The therapy stimulated expression of the inducible nitric oxide synthase, down-regulated transforming growth factor-ß1 and interleukin-8, reduced microvessel density, and resulted in apoptosis of endothelial cells in the lesions. These effects of AdmIFN-ß were partially diminished in mice treated with the antibodies.

Conclusions: These data suggest that macrophages play an important role in IFN-ß gene therapy and that intralesional delivery of the IFN-ß gene could be an effective therapy for clinically localized human prostate cancer.

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