CYCLOOXYGENASE-2 INHIBITION: A POTENTIAL MECHANISM FOR INCREASING THE EFFICACY OF BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY FOR BLADDER CANCER

Abstract

Intravesical bacillus Calmette-Guerin (BCG) therapy is the principal treatment for high risk, noninvasive urothelial carcinoma and carcinoma in situ of the bladder. However, up to 40% of patients fail to respond to this treatment. In this study the potential for inhibition of PGE2 production by BCG treated dendritic cells (DCs) was studied in the context of preferential polarization of the immune response toward a cancer clearing T-helper type 1 immune response. Murine bone marrow derived DCs were cultured with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. After 7 days the cells were stimulated with BCG. Cell surface expression of co-stimulatory molecules and phagocytic ability were measured by flow cytometry analysis to verify cell activation. The production of IL-10 and IL-12 was measured after DC stimulation with BCG in the presence of IL-10, prostaglandin E2(Cayman Chemical, Ann Arbor, Michigan), antiIL-10 antibody (Insight Biotechnology, Wembley, United Kingdom), NS-398 and indomethacin (Sigma, Poole, United Kingdom). Prostaglandin E2 stimulated a dose dependent increase in the levels of IL-10 produced by BCG activated DCs (p <0.01). IL-10 significantly decreased IL-12 production (p <0.001), while IL-10 blockade significantly increased IL-12 levels (p <0.05). The COX-2 selective inhibitor NS-398 caused a dose dependent increase in the concentration of IL-12 produced by BCG activated DCs (p <0.01). This effect was also seen with the partially selective COX-1 inhibitor indomethacin (p <0.05). The inhibition of PGE2 synthesis by COX inhibition favored the production of IL-12 by BCG activated DC. This potentially will result in the generation of a T-helper type 1, polarized T-cell response that may improve the efficacy of BCG therapy.