Inhibition of transforming growth factor-beta-mediated immunosuppression in tumor-draining lymph nodes augments antitumor responses by various immunologic cell types.

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-beta (TGF-beta), plays a critical role in suppressing these antitumor immune responses. We focused on TGF-beta-mediated immunosuppression in DLNs and examined whether local inhibition of TGF-beta augmented antitumor immune responses systemically in tumor-bearing mice models. For inhibition of TGF-beta-mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF-beta type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. near the established tumor. In DLNs, inhibition of TGF-beta suppressed the proliferation of regulatory T cells and increased the number of tumor antigen-specific CD4(+) or CD8(+) cells producing IFN-gamma. 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-beta-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-beta.

• Authors: Takuya Fujita, Koji Teramoto, Yoshitomo Ozaki, Jun Hanaoka, Noriaki Tezuka, Yasushi Itoh, Tohru Asai, Shozo Fujino, Keiichi Kontani, Kazumasa Ogasawara
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 12 Pg. 5142-50 (Jun 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19491278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Transforming Growth Factor beta
• DNA

Topics

• Animals
• Antigens, Neoplasm (immunology)
• DNA
• Female
• Immunosuppression Therapy
• Lymph Nodes (immunology)
• Mice
• Mice, Inbred C57BL
• Transforming Growth Factor beta (antagonists & inhibitors, genetics, physiology)