title: Yeast-Derived Particulate β-Glucan Treatment Subverts the Suppression of Myeloid-Derived Suppressor Cells (MDSC) by Inducing Polymorphonuclear MDSC Apoptosis and Monocytic MDSC Differentiation to APC in Cancer.
abstract: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. In this study, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole β-glucan particles (WGP; a ligand to engage and activate dectin-1, oral treatment in vivo) significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of polymorphonuclear MDSC but not monocytic MDSC (M-MDSC), and decreased polymorphonuclear MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80(+)CD11c(+) cells in vitro that served as potent APC to induce Ag-specific CD4(+) and CD8(+) T cell responses in a dectin-1-dependent manner. Additionally, Erk1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c(+) cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated s.c. with Lewis lung carcinoma cells. This effect was dependent on the dectin-1 receptor. Strikingly, patients with non-small cell lung carcinoma that had received WGP treatment for 10-14 d prior to any other treatment had a decreased frequency of CD14(-)HLA-DR(-)CD11b(+)CD33(+) MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202;
authors.forename: Sabrin H
authors.identifier: http://orcid.org/0000-0002-9708-6810
authors.initials: SH
authors.lastname: Albeituni
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; and.
authors.forename: Chuanlin
authors.initials: C
authors.lastname: Ding
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; and.
authors.forename: Min
authors.identifier: http://orcid.org/0000-0001-7095-1344
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; and.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Hu
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; and.
authors.forename: Fengling
authors.initials: F
authors.lastname: Luo
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; and.
authors.forename: Goetz
authors.initials: G
authors.lastname: Kloecker
authors.affiliation: Division of Thoracic Surgery, Department of Cardiovascular and 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, Louisville, KY 40202;
authors.forename: Huang-ge
authors.initials: HG
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202; Division of Hematology and Medical Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; and jun.yan@louisville.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002469:Cell Separation; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D015003:Yeasts; D047071:beta-Glucans / Q000276:immunology / Q000627:therapeutic use*; D000099181:Dectin-1
chemical_list: D037181:Lectins, C-Type; D047071:beta-Glucans; D000099181:Dectin-1
references.citation: J Immunol. 2005 Oct 1;175(7):4583-92
references.pmid: 16177103
references.citation: Nature. 2011 Apr 28;472(7344):471-5
references.pmid: 21525931
references.citation: Blood. 2011 Jun 23;117(25):6825-36
references.pmid: 21531981
references.citation: Clin Cancer Res. 2011 Nov 15;17(22):6992-7002
references.pmid: 21948231
references.citation: Cell Host Microbe. 2011 Dec 15;10(6):603-15
references.pmid: 22177564
references.citation: Nat Rev Immunol. 2012 Apr;12(4):253-68
references.pmid: 22437938
references.citation: Mol Ther. 2013 Jan;21(1):119-30
references.pmid: 22760540
references.citation: Nat Immunol. 2013 Mar;14(3):211-20
references.pmid: 23354483
references.citation: Cancer Immunol Immunother. 2013 May;62(5):909-18
references.pmid: 23589106
references.citation: J Immunol. 2008 Oct 15;181(8):5791-802
references.pmid: 18832739
references.citation: Eur J Immunol. 2013 May;43(5):1220-30
references.pmid: 23424024
references.citation: Lung Cancer. 2013 Sep;81(3):468-74
references.pmid: 23850196
references.citation: Cancer Immunol Immunother. 2013 Sep;62(9):1439-51
references.pmid: 23760662
references.citation: Cancer J. 2013 Nov-Dec;19(6):490-501
references.pmid: 24270348
references.citation: Ann N Y Acad Sci. 2014 Jun;1319:47-65
references.pmid: 24965257
references.citation: Cancer Res. 2005 Oct 15;65(20):9525-35
references.pmid: 16230418
references.citation: J Immunol. 2014 Oct 1;193(7):3308-21
references.pmid: 25143443
references.citation: J Clin Invest. 2006 Apr;116(4):916-28
references.pmid: 16543948
references.citation: J Immunol. 2006 Aug 1;177(3):1661-9
references.pmid: 16849475
references.citation: J Clin Invest. 2006 Oct;116(10):2777-90
references.pmid: 17016559
references.citation: Nat Immunol. 2007 Jan;8(1):39-46
references.pmid: 17159982
references.citation: Blood. 2008 Apr 15;111(8):4233-44
references.pmid: 18272812
references.citation: Cancer Res. 2008 Apr 15;68(8):2561-3
references.pmid: 18413722
references.citation: Cancer Res. 2008 Jul 1;68(13):5439-49
references.pmid: 18593947
references.citation: Neuro Oncol. 2011 Jun;13(6):591-9
references.pmid: 21636707
references.citation: Cancer Immunol Immunother. 2009 Jan;58(1):49-59
references.pmid: 18446337
references.citation: J Immunol. 2001 Jan 1;166(1):678-89
references.pmid: 11123353
references.citation: J Immunol. 2001 May 1;166(9):5398-406
references.pmid: 11313376
references.citation: Nature. 2001 Sep 6;413(6851):36-7
references.pmid: 11544516
references.citation: Nat Immunol. 2002 Nov;3(11):991-8
references.pmid: 12407406
references.citation: Clin Chim Acta. 2003 May;331(1-2):103-10
references.pmid: 12691870
references.citation: J Immunol. 2004 Jan 15;172(2):989-99
references.pmid: 14707072
references.citation: Annu Rev Immunol. 2004;22:329-60
references.pmid: 15032581
references.citation: J Immunol. 2004 Jul 15;173(2):797-806
references.pmid: 15240666
references.citation: Cancer Cell. 2004 Oct;6(4):409-21
references.pmid: 15488763
references.citation: J Immunol Methods. 1995 Jan 13;178(1):89-97
references.pmid: 7829869
references.citation: J Immunol. 1998 Nov 15;161(10):5313-20
references.pmid: 9820504
references.citation: J Immunol. 2009 Jan 1;182(1):240-9
references.pmid: 19109155
references.citation: Nat Rev Immunol. 2009 Mar;9(3):162-74
references.pmid: 19197294
references.citation: J Immunol. 2009 May 1;182(9):5693-701
references.pmid: 19380816
references.citation: Cancer Cell. 2009 Sep 8;16(3):183-94
references.pmid: 19732719
references.citation: Nat Rev Cancer. 2009 Nov;9(11):798-809
references.pmid: 19851315
references.citation: Cancer Res. 2010 Jan 1;70(1):68-77
references.pmid: 20028852
references.citation: Immunol Rev. 2010 Mar;234(1):335-52
references.pmid: 20193029
references.citation: J Exp Med. 2010 Oct 25;207(11):2439-53
references.pmid: 20876310
references.citation: Clin Cancer Res. 2010 Nov 1;16(21):5153-64
references.pmid: 20855461
references.citation: J Leukoc Biol. 2011 Feb;89(2):311-7
references.pmid: 21106641
references.citation: Immunity. 2011 Mar 25;34(3):385-95
references.pmid: 21376641
references.citation: Science. 2011 Mar 25;331(6024):1565-70
references.pmid: 21436444
references.citation: J Cancer Res Clin Oncol. 2010 Jan;136(1):35-45
references.pmid: 19572148