title: Dectin-1 Activation by a Natural Product β-Glucan Converts Immunosuppressive Macrophages into an M1-like Phenotype.
abstract: Tumor-associated macrophages (TAM) with an alternatively activated phenotype have been linked to tumor-elicited inflammation, immunosuppression, and resistance to chemotherapies in cancer, thus representing an attractive target for an effective cancer immunotherapy. In this study, we demonstrate that particulate yeast-derived β-glucan, a natural polysaccharide compound, converts polarized alternatively activated macrophages or immunosuppressive TAM into a classically activated phenotype with potent immunostimulating activity. This process is associated with macrophage metabolic reprograming with enhanced glycolysis, Krebs cycle, and glutamine utilization. In addition, particulate β-glucan converts immunosuppressive TAM via the C-type lectin receptor dectin-1-induced spleen tyrosine kinase-Card9-Erk pathway. Further in vivo studies show that oral particulate β-glucan treatment significantly delays tumor growth, which is associated with in vivo TAM phenotype conversion and enhanced effector T cell activation. Mice injected with particulate β-glucan-treated TAM mixed with tumor cells have significantly reduced tumor burden with less blood vascular vessels compared with those with TAM plus tumor cell injection. In addition, macrophage depletion significantly reduced the therapeutic efficacy of particulate β-glucan in tumor-bearing mice. These findings have established a new paradigm for macrophage polarization and immunosuppressive TAM conversion and shed light on the action mode of β-glucan treatment in cancer.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; Department of Immunology, Wuhan University School of Medicine, Wuhan 430072, China;
authors.forename: Min
authors.identifier: http://orcid.org/0000-0001-7095-1344
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; Department of Immunology, Wuhan University School of Medicine, Wuhan 430072, China;
authors.forename: Fengling
authors.initials: F
authors.lastname: Luo
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202;
authors.forename: Chuanlin
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202;
authors.forename: Sabrin
authors.initials: S
authors.lastname: Albeituni
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202;
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Hu
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202;
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202;
authors.forename: Yihua
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202;
authors.forename: Lacey
authors.initials: L
authors.lastname: McNally
authors.affiliation: Department of Pathology, University of Louisville School of Medicine, Louisville, KY 40202;
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Sanders
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202;
authors.forename: Dharamvir
authors.identifier: http://orcid.org/0000-0003-3482-8001
authors.initials: D
authors.lastname: Jain
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202;
authors.forename: Goetz
authors.initials: G
authors.lastname: Kloecker
authors.affiliation: Department of Cardiovascular Thoracic Surgery, University of Louisville, Louisville, KY 40202;
authors.forename: Michael
authors.initials: M
authors.lastname: Bousamra
authors.affiliation: Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202;
authors.forename: Huang-ge
authors.initials: HG
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, KY 40202; and.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Higashi
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; Department of Chemistry, University of Louisville, Louisville, KY 40202; and Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40202.
authors.forename: Andrew N
authors.identifier: http://orcid.org/0000-0003-1121-5106
authors.initials: AN
authors.lastname: Lane
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, KY 40202; and Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40202.
authors.forename: Teresa W-M
authors.initials: TW
authors.lastname: Fan
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202; jun.yan@louisville.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D062610:Fungal Polysaccharides / Q000737:chemistry / Q000494:pharmacology*; D037181:Lectins, C-Type / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012441:Saccharomyces cerevisiae / Q000737:chemistry*; D047071:beta-Glucans / Q000737:chemistry / Q000494:pharmacology*; D000099181:Dectin-1
chemical_list: D053468:CARD Signaling Adaptor Proteins; D062610:Fungal Polysaccharides; D037181:Lectins, C-Type; D047071:beta-Glucans; D000099181:Dectin-1; C513280:Card9 protein, mouse