title: Spontaneous elicitation of potent antitumor immunity and eradication of established tumors by administration of DNA encoding soluble transforming growth factor-beta II receptor without active antigen-sensitization.
abstract: Since immunity is generally suppressed by immunoregulatory factors, such as transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and vascular endothelial growth factor (VEGF), produced by tumor cells or stromal cells surrounding tumor cells, various kinds of cancer immunotherapy mostly fail to elicit potent antitumor immunity. Herein, we tested whether neutralization of TGF-beta can elicit strong antitumor immune responses and tumor regression in tumor-bearing mice. A plasmid DNA, pcDNA-sTGFbetaR/huIg, encoding a fusion protein consisting of the extracellular domain of TGF-beta type II receptor (TGFbetaRII) and the Fc portion of human IgG heavy chain, was injected through different routes into B6 mice carrying established tumors of E.G7 cells, which consist of the poorly immunogenic tumor cells EL4, transfected with the ovalbumin (OVA) gene. The frequency of OVA-specific cytotoxic T lymphocytes (CTL), in the treated mice. increased resulting in the tumor eradication and relapse-free survival in around 70% of the E.G7-bearing mice. In contrast, administration of mock DNA into E.G7-bearing mice did not elicit tumor-specific immune responses. Therefore, administration of DNA encoding TGFbetaRII allowed tumor-bearing hosts to elicit sufficiently potent antitumor immune responses without requirement of further active antigen-immunization. This strategy seems to be applicable to clinical therapy against cancer, because it is low-cost, safe, and easy to manipulate.
authors: Second Department of Surgery, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, 761-0793, Japan.
authors: Keiichi
authors: K
authors: Kontani
authors: Kiichi
authors: K
authors: Kajino
authors: Cheng-Long
authors: CL
authors: Huangi
authors: Shozo
authors: S
authors: Fujino
authors: Osamu
authors: O
authors: Taguchi
authors: Akira
authors: A
authors: Yamauchi
authors: Hiroyasu
authors: H
authors: Yokomise
authors: Kazumasa
authors: K
authors: Ogasawara
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology*; D010957:Plasmids; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D004247:DNA