Inhibition of transforming growth factor-beta-mediated immunosuppression in tumor-draining lymph nodes augments antitumor responses by various immunologic cell types.
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.
Fujita
Takuya
T
Department of Surgery, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga, Japan.
Teramoto
Koji
K
Ozaki
Yoshitomo
Y
Hanaoka
Jun
J
Tezuka
Noriaki
N
Itoh
Yasushi
Y
Asai
Tohru
T
Fujino
Shozo
S
Kontani
Keiichi
K
Ogasawara
Kazumasa
K
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D004247:DNA; D005260:Female; D007165:Immunosuppression Therapy; D008198:Lymph Nodes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
D000951:Antigens, Neoplasm; D016212:Transforming Growth Factor beta; D004247:DNA