Dendritic cell–activating vaccine adjuvants differ in the ability to elicit antitumor immunity due to an adjuvant-specific induction of immunosuppressive cells
Y Dang, WM Wagner, E Gad, L Rastetter… - Clinical cancer …, 2012 - AACR
Y Dang, WM Wagner, E Gad, L Rastetter, CM Berger, GE Holt, ML Disis
Clinical cancer research, 2012•AACRPurpose: 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 …
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 …
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. 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 (TH)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.
Conclusion: 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. Clin Cancer Res; 18(11); 3122–31. ©2012 AACR.
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