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

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

^* To whom correspondence should be addressed. E-mail: teramoto{at}belle.shiga-med.ac.jp.

	Abstract

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- (TGF-), plays a critical role in suppressing these antitumor immune responses. We focused on TGF-–mediated immunosuppression in DLNs and examined whether local inhibition of TGF- augmented antitumor immune responses systemically in tumor-bearing mice models. For inhibition of TGF-–mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF- type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. near the established tumor. In DLNs, inhibition of TGF- 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-–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-. [Cancer Res 2009;69(12):5142–50]

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