title: Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma.
abstract: OBJECTIVE
  Tumor-induced immunosuppression remains a significant obstacle that limits the efficacy of biological therapy for renal cell carcinoma. Here we evaluate the role of CD33 myeloid-derived suppressor cells (MDSC) in the regulation of T-cell responses in renal cell carcinoma patients. We also examine effect of all-trans-retinoic acid (ATRA) on MDSC-mediated immune suppression.
  
  
  METHODS
  CD33-positive myeloid cells were isolated from the peripheral blood of renal cell carcinoma patients with magnetic beads and tested in vitro for their ability to inhibit T-cell responses. T-cell function was evaluated using ELISPOT and CTL assays.
  
  
  RESULTS
  MDSC isolated from renal cell carcinoma patients, but not from healthy donors, were capable of suppressing antigen-specific T-cell responses in vitro through the secretion of reactive oxygen species and nitric oxide upon interaction with CTL. MDSC-mediated immune suppression and IFN-gamma down-regulation was reversible in vitro by exposing cells to the reactive oxygen species inhibitors. Moreover, ATRA was capable of abrogating MDSC-mediated immunosuppression and improving T-cell function by direct differentiation into antigen-presenting cell precursors.
  
  
  CONCLUSIONS
  These results may have significant implications regarding the future design of active immunotherapy protocols that may include differentiation agents as part of a multimodal approach to renal cell carcinoma immunotherapy.
authors.affiliation: Department of Urology, College of Medicine, University of Florida, Gainesville, Florida 32610-0247, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Kusmartsev
authors.forename: Zhen
authors.initials: Z
authors.lastname: Su
authors.forename: Axel
authors.initials: A
authors.lastname: Heiser
authors.forename: Jens
authors.initials: J
authors.lastname: Dannull
authors.forename: Evgeniy
authors.initials: E
authors.lastname: Eruslanov
authors.forename: Hubert
authors.initials: H
authors.lastname: Kübler
authors.forename: Donna
authors.initials: D
authors.lastname: Yancey
authors.forename: Philip
authors.initials: P
authors.lastname: Dahm
authors.forename: Johannes
authors.initials: J
authors.lastname: Vieweg
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007108:Immune Tolerance; D007680:Kidney Neoplasms / Q000276:immunology*; D022423:Myeloid Cells / Q000502:physiology*; D063268:Sialic Acid Binding Ig-like Lectin 3; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D006684:HLA-DR Antigens; D063268:Sialic Acid Binding Ig-like Lectin 3; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor