title: Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion.
abstract: Myeloid suppressor cells with high arginase activity are found in tumors and spleen of mice with colon and lung cancer. These cells, described as macrophages or immature dendritic cells, deplete arginine and impair T cell proliferation and cytokine production. Although arginase activity has been described in cancer patients, it is thought to originate from tumor cells metabolizing arginine to ornithine needed to sustain rapid cell proliferation. The goal of this study was to determine whether myeloid suppressor cells producing high arginase existed in renal cell carcinoma patients. Peripheral blood mononuclear cells from 123 patients with metastatic renal cell carcinoma, prior to treatment, were found to have a significantly increased arginase activity. These patients had a markedly decreased cytokine production and expressed low levels of T cell receptor CD3zeta chain. Cell separation studies showed that the increased arginase activity was limited to a specific subset of CD11b+, CD14-, CD15+ cells with a polymorphonuclear granulocyte morphology and markers, instead of macrophages or dendritic cells described in mouse models. Furthermore, these patients had low levels of arginine and high levels of ornithine in plasma. Depletion of the CD11b+, CD14- myeloid suppressor cells reestablished T cell proliferation and CD3zeta chain expression. These results showed, for the first time, the existence of suppressor myeloid cells producing arginase in human cancer patients. In addition, it supports the concept that blocking arginase may be an important step in the success of immunotherapy.
authors.affiliation: Stanley S. Scott Cancer Center, Department of Immunology and Microbiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Arnold H
authors.initials: AH
authors.lastname: Zea
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Claudia
authors.initials: C
authors.lastname: Hernandez
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Jovanny
authors.initials: J
authors.lastname: Zabaleta
authors.forename: David
authors.initials: D
authors.lastname: McDermott
authors.forename: David
authors.initials: D
authors.lastname: Quiceno
authors.forename: Amanda
authors.initials: A
authors.lastname: Youmans
authors.forename: Anne
authors.initials: A
authors.lastname: O'Neill
authors.forename: James
authors.initials: J
authors.lastname: Mier
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Ochoa
mesh_terms: D001119:Arginase / Q000096:biosynthesis*; D001120:Arginine / Q000097:blood; D039481:CD11b Antigen / Q000096:biosynthesis / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007680:Kidney Neoplasms / Q000097:blood / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation; D022423:Myeloid Cells / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D009362:Neoplasm Metastasis; D009952:Ornithine / Q000097:blood; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D039481:CD11b Antigen; D018950:Lipopolysaccharide Receptors; D001120:Arginine; D009952:Ornithine; D001119:Arginase