title: In vivo colocalization of antigen and CpG [corrected] within dendritic cells is associated with the efficacy of cancer immunotherapy.
abstract: Immunostimulatory cytidyl guanosyl (CpG) motifs are of great interest as cancer vaccine adjuvants. They act as potent inducers of Th1 responses, including the activation of cytotoxic CD8(+) T lymphocytes (CTL). Whereas animal models have provided clear evidence that CpG enhances antitumor immunity, clinical trials in humans have thus far been less successful. Applying cryosurgery as an instant in situ tumor destruction technique, we now show that timing of CpG administration crucially affects colocalization of antigen and CpG within EEA-1(+) and LAMP-1(+) compartments within dendritic cells in vivo. Moreover, antigen/CpG colocalization is directly correlated with antigen cross-presentation, the presence of CTL, and protective antitumor immunity. Thus, failure or success of CpG as a vaccine adjuvant may depend on colocalization of antigen/CpG inside DCs and hence on the timing of CpG administration. These data might aid in the design of future immunotherapeutic strategies for cancer patients.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nierkens
authors.forename: Martijn H
authors.initials: MH
authors.lastname: den Brok
authors.forename: Roger P M
authors.initials: RP
authors.lastname: Sutmuller
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Grauer
authors.forename: Erik
authors.initials: E
authors.lastname: Bennink
authors.forename: Mary E
authors.initials: ME
authors.lastname: Morgan
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: Theo J M
authors.initials: TJ
authors.lastname: Ruers
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
mesh_terms: D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D015226:Dinucleoside Phosphates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D015226:Dinucleoside Phosphates; C015772:CpG dinucleotide