title: Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer.
abstract: OBJECTIVE
  Myeloid-derived suppressor cells (MDSC) are one of the major factors responsible for immune suppression in cancer. Therefore, it would be important to identify effective therapeutic means to modulate these cells.
  
  
  METHODS
  We evaluated the effect of the synthetic triterpenoid C-28 methyl ester of 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO-Me; bardoxolone methyl) in MC38 colon carcinoma, Lewis lung carcinoma, and EL-4 thymoma mouse tumor models, as well as blood samples from patients with renal cell cancer and soft tissue sarcoma. Samples were also analyzed from patients with pancreatic cancer treated with CDDO-Me in combination with gemcitabine.
  
  
  RESULTS
  CDDO-Me at concentrations of 25 to 100 nmol/L completely abrogated immune suppressive activity of MDSC in vitro. CDDO-Me reduced reactive oxygen species in MDSCs but did not affect their viability or the levels of nitric oxide and arginase. Treatment of tumor-bearing mice with CDDO-Me did not affect the proportion of MDSCs in the spleens but eliminated their suppressive activity. This effect was independent of antitumor activity. CDDO-Me treatment decreased tumor growth in mice. Experiments with severe combined immunodeficient-beige mice indicated that this effect was largely mediated by the immune system. CDDO-Me substantially enhanced the antitumor effect of a cancer vaccines. Treatment of pancreatic cancer patients with CDDO-Me did not affect the number of MDSCs in peripheral blood but significantly improved the immune response.
  
  
  CONCLUSIONS
  CDDO-Me abrogated the immune suppressive effect of MDSCs and improved immune responses in tumor-bearing mice and cancer patients. It may represent an attractive therapeutic option by enhancing the effect of cancer immunotherapy.
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, Florida 33647, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Nagaraj
authors.forename: Je-In
authors.initials: JI
authors.lastname: Youn
authors.forename: Hannah
authors.initials: H
authors.lastname: Weber
authors.forename: Cristina
authors.initials: C
authors.lastname: Iclozan
authors.forename: Lily
authors.initials: L
authors.lastname: Lu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cotter
authors.forename: Colin
authors.initials: C
authors.lastname: Meyer
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Becerra
authors.forename: Mayer
authors.initials: M
authors.lastname: Fishman
authors.forename: Scott
authors.initials: S
authors.lastname: Antonia
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Rawal
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001119:Arginase / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D001119:Arginase