title: Therapeutic vaccination with dendritic cells pulsed with tumor-derived Hsp70 and a COX-2 inhibitor induces protective immunity against B16 melanoma.
abstract: Prophylactic immunization of mice with autologous tumor-derived heat shock proteins (Hsp) generates effective anti-tumor immunity. However, this approach is ineffective when used therapeutically, partly due to the immunosuppressive effects of the growing tumor. Here we sought to overcome this problem by therapeutic vaccination with dendritic cells (DC) pulsed with Hsp70 and a COX-2 inhibitor. We found that Hsp70 induces IL-6 and IL-10 production and suppressed expression of CD40 on DC. Incubation of DC with tumor-conditioned medium attenuated Hsp70-induced expression of CD80 and induced expression of COX-2. Inhibition of COX-2 partially reversed the stimulatory effect of Hsp70 on DC IL-6 and IL-10 production and enhanced expression of CD80 and MHC classes I and II. Therapeutic administration of DC pulsed in vitro with Hsp70 in the presence of a COX-2 inhibitor significantly reduced progression of B16 tumors in mice and significantly enhanced survival. This was associated with a reduction in the frequency of IL-10-producing CD4(+) T cells and enhancement of IFN-gamma-producing CD8(+) T cells. Our findings provide a novel immunotherapeutic approach against cancer based on attenuation of COX-2-mediated immunosuppression using in vitro modulated DC.
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Toomey
authors.forename: Helen
authors.initials: H
authors.lastname: Conroy
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Jarnicki
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Higgins
authors.forename: Caroline
authors.initials: C
authors.lastname: Sutton
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology*; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D016019:Survival Analysis
chemical_list: D018122:B7-1 Antigen; D019013:CD40 Antigens; D052246:Cyclooxygenase 2 Inhibitors; D018840:HSP70 Heat-Shock Proteins; D015850:Interleukin-6; D016753:Interleukin-10