Dendritic cell-activating vaccine adjuvants differ in the ability to elicit antitumor immunity due to an adjuvant- specific induction of immunosuppressive cells

Yushe Dang, Wolfgang M. Wagner, Ekram Gad, Lauren Rastetter, Carmen M. Berger, Gregory E. Holt, Mary L. Disis

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Purpose: 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. Experimental Design: 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. Wefurther 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 (TH)1, imiquimod induced elevated serum interleukin (IL)-10. Both MDSCand 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. Conclusion: Adjuvantsmay 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.

Original languageEnglish (US)
Pages (from-to)3122-3131
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number11
DOIs
StatePublished - Jun 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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