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.
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.
Kontani
Keiichi
K
Second Department of Surgery, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, 761-0793, Japan.
Kajino
Kiichi
K
Huangi
Cheng-Long
CL
Fujino
Shozo
S
Taguchi
Osamu
O
Yamauchi
Akira
A
Yokomise
Hiroyasu
H
Ogasawara
Kazumasa
K
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
D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D004247:DNA