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Inhibition of Transforming Growth Factor-β–Mediated Immunosuppression in Tumor-Draining Lymph Nodes Augments Antitumor Responses by Various Immunologic Cell Types

Departments of ¹ Surgery and ² Pathology, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, Japan; ³ Department of Surgery, University Hospital Mizonokuchi, Teikyo University School of Medicine, Takatsu-ku, Kawasaki, Kanagawa, Japan; and ⁴ Second Department of Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

Requests for reprints: Koji Teramoto, Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan. Phone: 81-77-548-2244; Fax: 81-77-544-2901; E-mail: teramoto{at}belle.shiga-med.ac.jp.

Key Words: TGF-β • tumor-draining lymph node • antitumor immune response • mouse model • molecular cancer therapy

Tumor-draining lymph nodes (DLN) are the most important priming sites for generation of antitumor immune responses. They are also the location where an immunosuppressive cytokine, transforming growth factor-β (TGF-β), plays a critical role in suppressing these antitumor immune responses. We focused on TGF-β–mediated immunosuppression in DLNs and examined whether local inhibition of TGF-β augmented antitumor immune responses systemically in tumor-bearing mice models. For inhibition of TGF-β–mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF-β type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. near the established tumor. In DLNs, inhibition of TGF-β suppressed the proliferation of regulatory T cells and increased the number of tumor antigen-specific CD4⁺ or CD8⁺ cells producing IFN-. Enhancement of antitumor immune responses in DLNs were associated with augmented tumor antigen-specific cytotoxic and natural killer activity in spleen as well as elevated levels of tumor-specific antibody in sera. The growth of the established metastatic as well as primary tumors was effectively suppressed via augmented antitumor immune responses. Inhibition of TGF-β–mediated immunosuppression in DLNs is significantly associated with augmented antitumor responses by various immunocompetent cell types. This animal model provides a novel rationale for molecular cancer therapeutics targeting TGF-β. [Cancer Res 2009;69(12):5142–50]