Introduction Experimental evidence suggests that induction of a polarized TH-1 response is optimal for bladder cancer immunotherapy. However, BCG therapy is known to induce dendritic cells (DC) to produce both IL-12 and IL-10 during antigen presentation resulting in the generation of a non-polarized population of helper T cells. The sub-optimal helper T cell environment engendered may attenuate the activation of cytotoxic T cells and explain the failure of cancer clearance in some patients. The objective of this study was to determine the potential of COX-2 inhibitors to synergize with intravesical BCG by polarizing towards TH-1, the poorly focused cell mediated immune response. Methods DCs were obtained by culture of CD1 murine femur leukocytes in media supplemented with 10ng/ml recombinant murine GM-CSF and 10ng/ml recombinant murine IL-4 for 7 days. DC maturation was assessed by phenotype (MHC-II, CD-80, CD-86 and CD-205 expression), and by phagocytic ability (Dextran endocytosis assay). DCs were stimulated with BCG in the presences of PGE2, IL-10, the COX-2 selective inhibitor NS-398, the COX-1 and COX-2 inhibitor Indomethacin, or an anti-IL-10 antibody. DC conditioned medium was analyzed for IL-12 and IL-10 by ELISA. Results PGE2 stimulates a dose-dependent increase in the levels of the pro-TH-2 cytokine IL-10 produced by BCG activated DC (p<0.01). Furthermore, PGE2, an immunomodulatory prostaglandin produced exclusively via the COX pathway, dose-dependently decreases DC production of the pro-TH-1 cytokine IL-12 by increasing the levels of IL-10 (p<0.01). The COX-2 selective inhibitor NS-398 causes a dose-dependent increase in the level of IL-12 production by BCG activated DCs (p<0.01); this response is mimicked by Indomethacin, a partially selective COX-1 inhibitor, but to a lesser extent (p<0.05). Conclusion The abrogation of PGE2 synthesis by COX-2 inhibition results in a polarized pro-TH-1 environment. The combination of a COX-2 inhibitor with standard intravesical BCG therapy may enhance the cell-mediated anti-tumor response.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]