175 ENHANCING DENDRITIC CELL VACCINES WITH LIGANDS FOR DECTIN-1 AND TOLL-LIKE RECEPTOR-9

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research (I)1 Apr 2013175 ENHANCING DENDRITIC CELL VACCINES WITH LIGANDS FOR DECTIN-1 AND TOLL-LIKE RECEPTOR-9 Yanping Wang, Nargess Hassanzadeh-Kiabi, Helen Goodridge, David Underhill, and Hyung Kim Yanping WangYanping Wang Los Angeles, CA More articles by this author , Nargess Hassanzadeh-KiabiNargess Hassanzadeh-Kiabi Los Angeles, CA More articles by this author , Helen GoodridgeHelen Goodridge Los Angeles, CA More articles by this author , David UnderhillDavid Underhill Los Angeles, CA More articles by this author , and Hyung KimHyung Kim Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1555AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cancer vaccines have the potential to target tumors while sparing normal tissue. Dectin-1 receptor plays an important role in activating a cellular immune response against fungal infection, providing a rational for evaluating Dectin-1 ligand as an adjuvant for cancer vaccines. Activation of toll-like receptors (TLRs), particularly TLR-3, 4 and 9, has been reported to produce robust antitumor immune responses. Therefore, Dectin stimulation was evaluated alone or in combination with TLR stimulate. METHODS To assess CD8 T cell responses, B16 lysate-pulsed DCs were co-cultured with lymphocytes from pmel-1 mice. Pmel-1 transgenic mice express CD8 T cells with specificity for a Db-restricted epitope from the melanoma tumor antigen gp10025-33. The effect of stimulating DCs with ligands for Dectin-1, TLR, or both was assessed by monitoring pmel-1 lymphocyte proliferation and activation. Antitumor activity was assessed in vivo using syngeneic mouse tumor models for melanoma and renal cell carcinoma. RESULTS Treating DCs with Dectin-1 ligand (β-glucan) alone did not increase CD8 T cell proliferation or IFN-ψ production. Furthermore, there was no significant effect on CD8 T cells when DCs were treated with β-glucan combined with TLR4 ligand (lipopolysaccharide) or TLR3 ligand (poly I:C). However, the combination of β-glucan and TLR9 ligand (unmethylated CpG oligonucleotides, CpG) increased CD8 lymphocyte proliferation significantly more than CpG or β-glucan alone. In fact, the increase in CD8 proliferation was greater than with β-glucan plus all 3 TLR ligands. The combination of β-glucan and CpG was significantly more effective than β-glucan alone in stimulating IFN-ψ production. Based on these results, the combination of β-glucan and CpG was evaluated for enhancing DC vaccines in vivo. Bone marrow derived DCs were pulsed with tumor lysate and stimulated with β-glucan, CpG or both, prior to injection in mice. Following two DC vaccine treatments, mice were subcutaneously challenged with B16 tumors. A tumor prevention model was used to unequivocally demonstrate that antitumor effects were immune mediated with no possibility of direct cytotoxic effect by β-glucan or CpG. None of the mice treated with β-glucan plus CpG grew tumor while all control mice rapidly grew tumor. These findings were replicated using the in vivo RENCA model for renal cell carcinoma. CONCLUSIONS Preclinical data suggests that tumor lysate-pulsed DC vaccines can be enhanced by stimulation of Dectin-1 and TLR-9. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e72 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yanping Wang Los Angeles, CA More articles by this author Nargess Hassanzadeh-Kiabi Los Angeles, CA More articles by this author Helen Goodridge Los Angeles, CA More articles by this author David Underhill Los Angeles, CA More articles by this author Hyung Kim Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...