title: IFN-γ regulates survival and function of tumor-induced CD11b+ Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1.
abstract: Myeloid derived suppressor cells (MDSCs) play a critical role in suppression of immune responses in cancer and inflammation. Here, we describe how regulation of Bcl2a1 by cytokines controls the suppressor function of CD11b(+) Gr-1(high) granulocytic MDSCs. Coculture of CD11b(+) Gr-1(high) granulocytic MDSCs with antigen-stimulated T cells and simultaneous blockade of IFN-γ by the use of anti-IFN-γ blocking antibody, IFN-γ(-/-) effector T cells, IFN-γR(-/-) MDSCs or STAT1(-/-) MDSCs led to upregulation of Bcl2a1 in CD11b(+) Gr-1(high) cells, improved survival, and enhanced their suppressor function. Molecular studies revealed that GM-CSF released by antigen-stimulated CD8(+) T cells induced Bcl2a1 upregulation, which was repressed in the presence of IFN-γ by a direct interaction of phosphorylated STAT-1 with the Bcl2a1 promotor. Bcl2a1 overexpressing granulocytic MDSCs demonstrated prolonged survival and enhanced suppressor function in vitro. Our data suggest that IFN-γ/ STAT1-dependent regulation of Bcl2a1 regulates survival and thereby suppressor function of granulocytic MDSCs.
authors.affiliation: GI-Malignancy Section, Thoracic and GI-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: José
authors.initials: J
authors.lastname: Medina-Echeverz
authors.forename: Lydia A
authors.initials: LA
authors.lastname: Haile
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.forename: Jaba
authors.initials: J
authors.lastname: Gamrekelashvili
authors.forename: Chi
authors.initials: C
authors.lastname: Ma
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Métais
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Firouzeh
authors.initials: F
authors.lastname: Korangy
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D039481:CD11b Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D022423:Myeloid Cells / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology*; D019707:Receptors, Chemokine / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: C096816:BCL2-related protein A1; D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D019707:Receptors, Chemokine; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Bcl2a1; G-MDSC; GM-CSF; IFN-γ; Immunotherapy; Vaccine