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Suppression of Tumor Metastasis by Blockade of Transforming Growth Factor ß Signaling in Bone Marrow Cells through a Retroviral-mediated Gene Therapy in Mice¹

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 [A. H. S., W. B. T., S. D. K., V. C. L., C. L.]; Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892 [S-J. K.]; Department of Biology, Massachusetts Institute of Technology, Cambridge Massachusetts 02139 [L. V. P.]; Department of Urology, Mayo Clinic, Rochester, Minnesota 55905 [E. K.]; and Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030 [N. M. G.]

Transforming growth factor B (TGF-ß) is a potent immunosuppressive cytokine that is frequently associated with mechanisms of tumor escape from immunosurveillance. We report that transplantation of murine bone marrow (BM) expressing a dominant-negative TGF-ß type II receptor (TßRIIDN) leads to the generation of mature leukocytes capable of a potent antitumor response in vivo. Hematopoietic precursors in murine BM from donor mice were rendered insensitive to TGF-ß via retroviral expression of the TßRIIDN construct and were transplanted in C57BL/6 mice before tumor challenge. After i.v. administration of 5 x 10⁵ B16-F10 murine melanoma cells into TßRIIDN-BM transplanted recipients, survival of challenged mice at 45 days was 70% (7 of 10) versus 0% (0 of 10) for vector-control treated mice, and surviving TßRIIDN-BM mice showed a virtual absence of metastatic lesions in the lung. We also investigated the utility of the TGF-ß-targeted approach in a mouse metastatic model of prostate cancer, TRAMP-C2. Treatment of male C57BL/6 mice with TßRIIDN-BM resulted in the survival of 80% (4 of 5) of recipients versus 0% (0 of 5) in green fluorescent protein-BM recipients or wild-type controls. Cytolytic T-cell assays indicate that a specific T-cell response against B16-F10 cells was generated in the TßRIIDN-BM-treated mice, suggesting that a gene therapy approach to inducing TGF-ß insensitivity in transplanted BM cells may be a potent anticancer therapy.

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