Therapeutic anti-tumor response induced with epitope-pulsed fibroblasts genetically engineered for B7.1 expression and IFN-gamma secretion.

Abstract

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.