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Introduction: Immunotherapy via dendritic cells (DC) has shown promise as a novel approach to hormone-refractory prostate cancer. DC are the major antigen-presenting cells and regulators of the immune response. We have previously demonstrated that prostate cancer induces DC apoptosis, which could be one mechanism of tumor escape from immune surveillance. We also demonstrated the presence of endothelin receptors on DC, and that blockade of endothelin B (ETB) receptors decreases DC apoptosis, while it may enhance their antigen presenting ability. The purpose of the current study was to determine whether ETB blockade also enhances DC antitumor activity in a murine prostate cancer model.

Methods: Tumors were induced by subcutaneous injection of 25,000 RM-1 murine prostate cancer cells into groups (n=5) of the C57BL/6 mice. When tumors became palpable (day 6), treatment was initiated with injection of 1.5x106 bone marrow derived DC into the tumor. DC were prepared as usual in complete media in the presence of GM-CSF and IL-4 for 7 days. Group 1 received Hank’s solution (control); Group 2 - unmodified DC; Group 3 -DC treated with TNF-α during the last 48 hours; Group 4 - DC treated with TNF-α and ETB receptor antagonist BQ-788 during the last 48 hours (our previous studies have shown the increased expression of endothelin receptors after the stimulation of DCs with TNF-α). Two further injections were performed on days 9 and 12. Tumor size was assessed starting from day 14 until animal sacrifice.

Results: By day 24, mean tumor size reached 1796±166 mm3 in the Group 1 (control), 1556±186 mm3 in the Group2, 1508+166 mm3 in the group 3, and 397±186 mm3 in Group 4 (P<0.001 versus control). Difference in mean tumor size became significant starting from day 20.

Conclusions: We hypothesize that ETB receptor blockade protects DC from apoptosis and may increase their antigen-presenting capability. Our data suggest that ETB receptor blockade also promotes DC antitumor activity in vivo. We plan to extend these studies into human clinical trials, using autologous dendritic cells.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA