title: Enhanced activation of human dendritic cells by inducible CD40 and Toll-like receptor-4 ligation.
abstract: Despite the potency of dendritic cells (DC) as antigen-presenting cells for priming adaptive immunity, DC-based cancer vaccines have been largely insufficient to effectively reduce tumor burden or prevent tumor progression in most patients. To enhance DC-based vaccines, we used the combination of a synthetic ligand-inducible CD40 receptor (iCD40) along with Toll-like receptor-4 (TLR-4) ligation in human monocyte-derived DCs. The iCD40 receptor permits targeted, reversible activation of CD40 in vivo, potentially bypassing the essential role of CD4(+) T cells for activation of DCs. As a rigorous preclinical study of this approach, we evaluated key parameters of DC activation and function. Whereas neither iCD40 nor TLR-4 signaling alone led to high levels of interleukin (IL)-12p70 and IL-6, using iCD40 in combination with lipopolysaccharide (LPS) or monophosphoryl lipid A led to strongly synergistic production of both. Furthermore, this approach led to high expression of DC maturation markers, epitope-specific CTL and T helper 1 responses, as well as DC migration in vitro and in vivo. Moreover, use of iCD40-modified and LPS-stimulated DCs led to targeted expansion of autologous T cells against tumor-associated antigens, including prostate-specific membrane antigen, and elimination of preestablished tumors, supporting this technology as a potent strategy for DC-based cancer immunotherapy.
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lapteva
authors.forename: Mamatha R
authors.initials: MR
authors.lastname: Seethammagari
authors.forename: Brent A
authors.initials: BA
authors.lastname: Hanks
authors.forename: Jianghong
authors.initials: J
authors.lastname: Jiang
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Levitt
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Slawin
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology*; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D016764:Cell Polarity; D003713:Dendritic Cells / Q000276:immunology*; D043425:Glutamate Carboxypeptidase II / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D054400:Receptors, CCR7 / Q000032:analysis; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D000954:Antigens, Surface; C515370:CCR7 protein, human; D019013:CD40 Antigens; D019496:Cancer Vaccines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D054400:Receptors, CCR7; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D018664:Interleukin-12; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II