Therapeutic anti-tumor response induced with epitope-pulsed fibroblasts genetically engineered for B7.1 expression and IFN-gamma secretion.
Mouse fibroblasts (H-2(b)) were genetically engineered to express a co-stimulatory B7.1 and an IFN-gamma (Fb/IFN-gamma/B7.1). The Fb/IFN-gamma/B7.1 cells were then pulsed with an ovalbumin epitope (amino acids 257-264, SIINFEKL, H-2K(b)-restricted) as a model antigen (Fb/IFN-gamma/B7.1/OVA) and tested for the induction of OVA-specific cytotoxic T lymphocytes (CTLs) in C57BL/6 mice (H-2(b)). Genetically engineered fibroblasts lacking either IFN-gamma or B7.1 were constructed and used as controls. Immunization with the Fb/IFN-gamma/B7.1/OVA cells induced strong cytotoxic activity against OVA-expressing EL4 (EG7) tumor cells but not against other H-2(b) tumor cells, such as EL4, C1498, and B16F1. The magnitude of the cytotoxic response in mice with the Fb/IFN-gamma/B7.1/OVA cells was significantly higher than that in mice immunized with any other cell construct. CD8(+) T cells with OVA-specific cytotoxic activity were predominant in mice immunized with Fb/IFN-gamma/B7.1/OVA cells. Furthermore, treatment with Fb/IFN-gamma/B7.1/OVA cells significantly prolonged the survival period of EG7 tumor-bearing mice. Anti-tumor CTL immunity by the Fb/IFN-gamma/B7.1/OVA cells could be induced without the help of host antigen-presenting cells, CD4(+) T cells, or NK1.1(+) cells. Our results suggest that fibroblasts can be genetically modified into efficient antigen-presenting cells for the induction of antigen-specific CTL response in cancer immunotherapy.
Kim
T S
TS
College of Pharmacy, Chonnam National University, Kwangju, Republic of Korea. taekim@chonnam.chonnam.ac.kr
Chung
S W
SW
Kim
S H
SH
Kang
S N
SN
Kang
B Y
BY
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology; D018076:DNA, Complementary / Q000235:genetics; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D015316:Genetic Therapy; D006183:H-2 Antigens / Q000276:immunology*; D007114:Immunization; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism*; D008223:Lymphoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018076:DNA, Complementary; D000939:Epitopes; D006183:H-2 Antigens; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma; D010047:Ovalbumin; D003165:Complement System Proteins