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[Cancer Research 63, 1860-1864, April 15, 2003]
© 2003 American Association for Cancer Research

Immunology

Transforming Growth Factor ß Inhibits the Antigen-Presenting Functions and Antitumor Activity of Dendritic Cell Vaccines1

James J. Kobie, Rita S. Wu2, Robert A. Kurt, Sunming Lou, Miranda K. Adelman, Luke J. Whitesell, Lalitha V. Ramanathapuram, Carlos L. Arteaga and Emmanuel T. Akporiaye3

Departments of Microbiology and Immunology [J. J. K., R. S. W., S. L., M. K. A., L. V. R., E. T. A.] and Pediatrics [L. J. W.], University of Arizona, Tucson, Arizona 85724; Department of Biology, Lafayette College, Easton, Pennsylvania 18042 [R. A. K.]; and Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37332 [C. L. A.]

Dendritic cell (DC)-based vaccines have exhibited minimal effectiveness in treating established tumors, likely because of factors present in the tumor microenvironment. One such factor is transforming growth factor ß (TGF-ß), a cytokine that is produced by numerous tumor types and has been demonstrated to impair DC functions in vitro. We have evaluated the effect of TGF-ß on the immunostimulatory activities of DCs. We demonstrate that TGF-ß exposure inhibits the ability of DCs to present antigen, stimulate tumor-sensitized T lymphocytes, and migrate to draining lymph nodes. Neutralization of TGF-ß using the TGF-ß-neutralizing monoclonal antibody 2G7 enhanced the ability of DC vaccines to inhibit the growth of established 4T1 murine mammary tumors. Treatment of 4T1 tumors transduced with the antisense TGF-ß transgene (4T1-asT) with the combination of DC and 2G7 monoclonal antibody inhibited tumor growth and resulted in complete regression of tumors in 40% of the mice. These results demonstrate that neutralization of TGF-ß in tumor-bearing mice enhances the efficacy of DC-based vaccines.




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