title: Ex vivo generation of myeloid-derived suppressor cells that model the tumor immunosuppressive environment in colorectal cancer.
abstract: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in tumor-bearing subjects and which strongly inhibit anti-cancer immune responses. To study the biology of MDSC in colorectal cancer (CRC), we cultured bone marrow cells in conditioned medium from CT26 cells, which are genetically modified to secrete high levels of granulocyte-macrophage colony-stimulating factor. This resulted in the generation of high numbers of CD11b(+) Ly6G(+) granulocytic and CD11b(+) Ly6C(+) monocytic MDSC, which closely resemble those found within the tumor but not the spleen of CT26 tumor-bearing mice. Such MDSC potently inhibited T-cell responses in vitro, a process that could be reversed upon blocking of arginase-1 or inducible nitric oxide synthase (iNOS). We confirmed that inhibition of arginase-1 or iNOS in vivo resulted in the stimulation of cytotoxic T-cell responses. A delay in tumor growth was observed upon functional repression of both enzymes. These data confirm the role of MDSC as inhibitors of T-cell-mediated immune responses in CRC. Moreover, MDSC differentiated in vitro from bone marrow cells using conditioned medium of GM-CSF-secreting CT26 cells, represent a valuable platform to study/identify drugs that counteract MDSC activities.
authors: UZ Brussel, Department of Radiotherapy, Vrije Universiteit Brussel, Brussels, Belgium.|Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Inès
authors: I
authors: Dufait
authors: UZ Brussel, Department of Radiotherapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Julia Katharina
authors: JK
authors: Schwarze
authors: Navarrabiomed-Fundaçion Miguel Servet, Immunomodulation Group, Pamplona, Spain.|Division of Infection and Immunity, University College London, London, UK.
authors: Therese
authors: T
authors: Liechtenstein
authors: UZ Brussel, Department of Radiotherapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Wim
authors: W
authors: Leonard
authors: UZ Brussel, Department of Radiotherapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Heng
authors: H
authors: Jiang
authors: Navarrabiomed-Fundaçion Miguel Servet, Immunomodulation Group, Pamplona, Spain.|Division of Infection and Immunity, University College London, London, UK.
authors: David
authors: D
authors: Escors
authors: UZ Brussel, Department of Radiotherapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Mark
authors: M
authors: De Ridder
authors: Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Karine
authors: K
authors: Breckpot
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: CRC; GM-CSF; MDSC; arginase-1; inducible nitric oxide synthase