1. ¹Department of Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, Ohio 45267-0521, USA
2. ²Department of Otolaryngology, University of Cincinnati, Cincinnati, Ohio 45267, USA
3. ³NIDCD Building 10, Room 5D55, Rockville, Maryland 20892, USA
4. ⁴Division of Medical Oncology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA

Correspondence: Dr Peter J Stambrook, Department of Cell Biology, Neurobiology, and Anatomy, Vontz Center for Molecular Studies, College of Medicine, University of Cincinnati, 3125 Eden Avenue, Cincinnati, OH 45267-0521, USA. E-mail: peter.stambrook@uc.edu

Received 10 September 2002.

Abstract

The Flt3 ligand (Flt3-L) manifests antitumor activity, presumably due to its capacity to recruit dendritic cells and cause their proliferation. To assess whether local production of Flt3-L can mediate a "distant bystander" effect, murine B4B8 squamous cell carcinoma cells were transfected with a plasmid encoding a secretory form of Flt3-L to produce B4B8FL cells. Similarly, B4B8FL and B4B8 cells were transfected with herpes simplex virus thymidine kinase (HSVTK) to produce B4B8TK and B4B8FL/TK cells, which should be sensitive to ganciclovir (GCV), to know whether the effects of Flt3-L and HSVTK/GCV would be synergistic. To test for a distant bystander effect in vivo, B4B8FL, B4B8TK, and B4B8FL/TK cells were injected subcutaneously into the left flank of syngeneic Balb/c mice, and naïve B4B8 cells were injected into the right flank. The formation of tumors derived from B4B8FL and B4B8FL/TK cells was significantly delayed in both flanks compared with naïve B4B8 and B4B8TK cells. Growth of B4B8TK tumors in the ipsilateral flank was retarded following GCV treatment, but in contrast to B4B8FL and B4B8FL/TK cells, no distant bystander effect in the contralateral flank was observed. Immunohistochemistry showed lymphocytic infiltrates in both flanks of the B4B8FL and B4B8FL/TK groups. The data indicate that in these cells, local secretion of Flt3-L is sufficient to evoke a distant bystander effect but that expression of HSVTK, even after GCV administration, is not. Furthermore, the combination of local Flt3-L and HSVTK production, together with GCV administration, does not enhance the distant bystander effect produced by Flt3-L alone.