title: Myeloid-derived suppressor cells reveal radioprotective properties through arginase-induced l-arginine depletion.
abstract: High arginase-1 (Arg) expression by myeloid-derived suppressor cells (MDSC) is known to inhibit antitumor T-cell responses through depletion of l-arginine. We have previously shown that nitric oxide (NO), an immune mediator produced from l-arginine, is a potent radiosensitizer of hypoxic tumor cells. This study therefore examines whether Arg(+) overexpressing MDSC may confer radioresistance through depleting the substrate for NO synthesis.
  
  
  
  MDSC and Arg expression were studied in preclinical mouse CT26 and 4T1 tumor models and further validated in rectal cancer patients in comparison with healthy donors. The radioprotective effect of MDSC was analyzed in hypoxic tumor cells with regard to l-arginine depletion.
  
  
  
  In both mouse tumors and cancer patients, MDSC expansion was associated with Arg activation causing accelerated l-arginine consumption. l-Arginine depletion in turn profoundly suppressed the capacity of classically activated macrophages to synthesize NO resulting in impaired tumor cell radiosensitivity. In advanced cT3-4 rectal cancer, circulating neutrophils revealed Arg overexpression approaching that in MDSC, therefore mounting a protumor compartment wherein Arg(+) neutrophils increased from 17% to over 90%.
  
  
  
  Protumor Arg(+) MDSC reveal a unique ability to radioprotect tumor cells through l-arginine depletion, a common mechanism behind both T-cell and macrophage inhibition.
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Leonard
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium; Department of Immunology-Physiology, Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Inès
authors.initials: I
authors.lastname: Dufait
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Julia Katharina
authors.initials: JK
authors.lastname: Schwarze
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Kalun
authors.initials: K
authors.lastname: Law
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Engels
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Heng
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Van den Berge
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gevaert
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Storme
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Valeri
authors.initials: V
authors.lastname: Verovski
authors.affiliation: Department of Immunology-Physiology, Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
authors.affiliation: Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address: mark.deridder@uzbrussel.be.
authors.forename: Mark
authors.initials: M
authors.lastname: De Ridder
mesh_terms: D000818:Animals; D001119:Arginase / Q000502:physiology*; D001120:Arginine / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D008264:Macrophages / Q000502:physiology; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D012004:Rectal Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D009569:Nitric Oxide; D001120:Arginine; D001119:Arginase
keywords: Arginase; Hypoxic radiosensitivity; MDSC; Rectal cancer; l-Arginine