title: Dendritic cell-activating vaccine adjuvants differ in the ability to elicit antitumor immunity due to an adjuvant-specific induction of immunosuppressive cells.
abstract: OBJECTIVE
  We questioned whether the vaccine adjuvant combination of TLR-7 ligand agonist, imiquimod, with granulocyte macrophage colony-stimulating factor (GM-CSF) would result in enhanced dendritic cell recruitment and activation with increased antigen-specific immunity as compared with either adjuvant used alone.
  
  
  METHODS
  The adjuvant effects of GM-CSF and imiquimod were studied in ovalbumin (OVA) and MMTVneu transgenic mice using peptide-based vaccines. Type I immunity, serum cytokines, myeloid-derived suppressive cells (MDSC), and regulatory T cells (Treg) levels were examined.
  
  
  RESULTS
  Both GM-CSF and imiquimod equally induced local accumulation and activation of dendritic cells. Both adjuvants effectively enhanced OVA-specific T-cell responses. We further evaluated the antitumor efficacy of adjuvant GM-CSF and imiquimod immunizing against murine insulin-like growth factor-binding protein-2 (IGFBP-2), a nonmutated oncoprotein overexpressed in the tumors of MMTVneu transgenic mice. Tumor growth was significantly inhibited in the mice receiving IGFBP-2 peptides with GM-CSF (P = 0.000), but not in imiquimod vaccine-treated groups (P = 0.141). Moreover, the addition of imiquimod to GM-CSF negated the antitumor activity of the vaccine when GM-CSF was used as the sole adjuvant. While GM-CSF stimulated significant levels of antigen-specific T-helper cell (T(H))1, imiquimod induced elevated serum interleukin (IL)-10. Both MDSC and Tregs were increased in the imiquimod-treated but not GM-CSF-treated groups (P = 0.000 and 0.006, respectively). Depleting MDSC and Treg in animals immunized with imiquimod and IGFBP-2 peptides restored antitumor activity to the levels observed with vaccination using GM-CSF as the sole adjuvant.
  
  
  CONCLUSIONS
  Adjuvants may induce regulatory responses in the context of a self-antigen vaccine. Adjuvant triggered immunosuppression may limit vaccine efficacy and should be evaluated in preclinical models especially when contemplating combination approaches.
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, WA 98109, USA. ydang@u.washington.edu
authors.forename: Yushe
authors.initials: Y
authors.lastname: Dang
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Wagner
authors.forename: Ekram
authors.initials: E
authors.lastname: Gad
authors.forename: Lauren
authors.initials: L
authors.lastname: Rastetter
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Berger
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Holt
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000634:Aminoquinolines / Q000276:immunology; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D000077271:Imiquimod; D007165:Immunosuppression Therapy; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000276:immunology; D007369:Interferon Inducers / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D019496:Cancer Vaccines; D018971:Insulin-Like Growth Factor Binding Protein 2; D007369:Interferon Inducers; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010047:Ovalbumin; D000077271:Imiquimod