Generation of tumor-specific cytotoxic T lymphocyte and prolongation of the survival of tumor-bearing mice using interleukin-18-secreting fibroblasts loaded with an epitope peptide.
There is currently much interest in generating cytotoxic T lymphocyte (CTL) responses against tumor antigens as a therapy for cancer. In this study mouse fibroblasts (H-2(b)) were genetically modified to express a costimulatory B7.1 and a mature interleukin (IL)-18, and then loaded with an ovalbumin (OVA) epitope (SIINFEKL, H-2K(b) restricted) as a model antigen, and tested for the induction of OVA-specific CTLs in C57BL/6 mice (H-2(b)). The genetically modified fibroblasts lacking either IL-18 or B7.1 were also constructed. Immunization with the IL-18/B7.1-transfected fibroblasts induced strong cytotoxic activities against OVA-expressing EL4 (EG7) tumor cells, but not against other H-2(b) tumor cells such as EL4, C1498, and B16F1 cells. The magnitude of the cytotoxic response in mice with the IL-18/B7.1-transfected fibroblasts was significantly higher than the response in mice immunized with any other cell constructs. CD8(+) T cells with OVA-specific cytotoxic activities were predominant in mice immunized with the IL-18/B7.1-transfected fibroblasts. Furthermore, treatment with the IL-18/B7.1-transfected fibroblasts significantly prolonged the survival period of EG7 tumor-bearing mice. Anti-tumor CTL immunity by the IL-18/B7.1-transfected fibroblasts could be induced without the help of host antigen-presenting cells (APCs) and NK1.1(+) cells, whereas partially decreased by the depletion of CD4(+) T cells at the inductive stage. These results support the ability of IL-18/B7.1 gene transfer to enhance the antigen-presenting capacity of fibroblasts for inducing antigen-specific CTL response.
Chung
Su W
SW
Department of Pharmacy, College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Kwangju 500-757, South Korea.
Cohen
Edward P
EP
Kim
Tae S
TS
D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation*; D020382:Interleukin-18 / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000939:Epitopes; D020382:Interleukin-18; D010446:Peptide Fragments; D010047:Ovalbumin