title: Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived β-glucans.
abstract: β-glucans have been reported to function as a potent adjuvant to stimulate innate and adaptive immune responses. However, β-glucans from different sources are differential in their structure, conformation, and thus biologic activity. Different preparations of β-glucans, soluble versus particulate, further complicate their mechanism of action. Here we show that yeast-derived particulate β-glucan activated dendritic cells (DCs) and macrophages via a C-type lectin receptor dectin-1 pathway. Activated DCs by particulate β-glucan promoted Th1 and cytotoxic T-lymphocyte priming and differentiation in vitro. Treatment of orally administered yeast-derived particulate β-glucan elicited potent antitumor immune responses and drastically down-regulated immunosuppressive cells, leading to the delayed tumor progression. Deficiency of the dectin-1 receptor completely abrogated particulate β-glucan-mediated antitumor effects. In contrast, yeast-derived soluble β-glucan bound to DCs and macrophages independent of the dectin-1 receptor and did not activate DCs. Soluble β-glucan alone had no therapeutic effect but significantly augmented antitumor monoclonal antibody-mediated therapeutic efficacy via a complement activation pathway but independent of dectin-1 receptor. These findings reveal the importance of different preparations of β-glucans in the adjuvant therapy and allow for the rational design of immunotherapeutic protocols usable in clinical trials.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Chunjian
authors.initials: C
authors.lastname: Qi
authors.forename: Yihua
authors.initials: Y
authors.lastname: Cai
authors.forename: Lacey
authors.initials: L
authors.lastname: Gunn
authors.forename: Chuanlin
authors.initials: C
authors.lastname: Ding
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Goetz
authors.initials: G
authors.lastname: Kloecker
authors.forename: Keqing
authors.initials: K
authors.lastname: Qian
authors.forename: John
authors.initials: J
authors.lastname: Vasilakos
authors.forename: Shinobu
authors.initials: S
authors.lastname: Saijo
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: John R
authors.initials: JR
authors.lastname: Yannelli
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
mesh_terms: D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D037181:Lectins, C-Type; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000276:immunology; D010587:Phagocytosis; D012441:Saccharomyces cerevisiae / Q000737:chemistry* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D047071:beta-Glucans / Q000276:immunology* / Q000302:isolation & purification / Q000627:therapeutic use*; D000099181:Dectin-1
chemical_list: D000276:Adjuvants, Immunologic; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D047071:beta-Glucans; D000099181:Dectin-1