Flt3 ligand antitumor activity in a murine breast cancer model: A comparison with granulocyte-macrophage colony-stimulating factor and a potential mechanism of action

We have shown that Flk2/Flt3 ligand (Flt3L)-transduced tumor vaccine induce s transferable T cell protection against a murine breast cancer cell line, but a direct comparison with the potent effector GM-CSF, the activity again st preestablished tumors, and the mechanism of antitumor response in this b reast cancer model are not known. We compared vaccination with C3L5 cells e xpressing Flt3L (C3Lt-Flt3L) and GM-CSF (C3L5-GMCSF) by injecting 1 x 10(4) cells subcutaneously into the chest wall and then, after 4 weeks, challeng ing the contralateral chest of tumor-free mice with parental C3L5 cells. C3 L5-Flt3L and C3L5-GMCSF had reduced in vivo growth rates (25% tumor formati on each) compared with 100% tumor formation of C3L5 cells expressing only n eomycin phosphotransferase (C3L5-G1N). However, when tumor-free animals wer e challenged with parental C3L5 cells, C3L5-Flt3L vaccination was significa ntly better at preventing tumor growth (p < 0.05) than C3L5-GMCSF vaccinati on (33% of C3L5-Flt3L-vaccinated animals developed tumor compared with 77% of C3L5-GMCSF-vaccinated animals). Adoptive transfer of immunity for both v accines was demonstrated; splenic T cells from tumor-free mice protected na ive mice from parental tumor challenge. To simulate minimal disease, parent al C3L5 cells at two concentrations thigh, 5 x 10(3) cells; or low, 1 x 10( 3) cells) were injected into the contralateral chest wall 4 days prior to t reatment with C3L5-G1N or C3L5-Flt3L. C3L5-Flt3L treatment decreased contra lateral parental tumor formation thigh, 67% tumor free; low, 90% tumor free ) compared with C3L5-G1N treatment thigh and low, 0% tumor free). Immunodep letion of activated natural killer cells with anti-asialo-GM(1) blocked C3L 5-Flt31L- and C3L5 plus soluble Flt3L-mediated antitumor activity. Thus, Fl t3L-transduced tumor cells manifest potent antitumor activity, apparently m ediated, at least partially, by natural killer cells.