title: Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma.
abstract: BACKGROUND
  Multiple myeloma (MM) is a plasma cell malignancy with a multifaceted immune dysfunction. Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan into kynurenine (KYN), which inhibits effector T cells and promote regulatory T-cell (Treg) differentiation. It is presently unknown whether MM cells express IDO1 and whether IDO1 activity correlates with immune system impairment.
  
  
  METHODS
  We investigated IDO1 expression in 25 consecutive patients with symptomatic MM and in 7 patients with either monoclonal gammopathy of unknown significance (MGUS; n=3) or smoldering MM (SMM; n=4). IDO1-driven tryptophan breakdown was correlated with the release of hepatocyte growth factor (HGF) and with the frequency of Treg cells and NY-ESO-1-specific CD8(+) T cells.
  
  
  RESULTS
  KYN was increased in 75% of patients with symptomatic MM and correlated with the expansion of CD4(+)CD25(+)FoxP3(+) Treg cells and the contraction of NY-ESO-1-specific CD8(+) T cells. In vitro, primary MM cells promoted the differentiation of allogeneic CD4(+) T cells into bona fide CD4(+)CD25(hi)FoxP3(hi) Treg cells and suppressed IFN-γ/IL-2 secretion, while preserving IL-4 and IL-10 production. Both Treg expansion and inhibition of Th1 differentiation by MM cells were reverted, at least in part, by D,L-1-methyl-tryptophan, a chemical inhibitor of IDO. Notably, HGF levels were higher within the BM microenvironment of patients with IDO(+) myeloma disease compared with patients having IDO(-) MM. Mechanistically, the antagonism of MET receptor for HGF with SU11274, a MET inhibitor, prevented HGF-induced AKT phosphorylation in MM cells and translated into reduced IDO protein levels and functional activity.
  
  
  CONCLUSIONS
  These data suggest that IDO1 expression may contribute to immune suppression in patients with MM and possibly other HGF-producing cancers.
authors.affiliation: Department of Gynecology, Catholic University Med. School, Rome, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Bonanno
authors.forename: Andrea
authors.initials: A
authors.lastname: Mariotti
authors.forename: Annabella
authors.initials: A
authors.lastname: Procoli
authors.forename: Valentina
authors.initials: V
authors.lastname: Folgiero
authors.forename: Daniela
authors.initials: D
authors.lastname: Natale
authors.forename: Luca
authors.initials: L
authors.lastname: De Rosa
authors.forename: Ignazio
authors.initials: I
authors.lastname: Majolino
authors.forename: Linda
authors.initials: L
authors.lastname: Novarese
authors.forename: Alberto
authors.initials: A
authors.lastname: Rocci
authors.forename: Manuela
authors.initials: M
authors.lastname: Gambella
authors.forename: Marilena
authors.initials: M
authors.lastname: Ciciarello
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Raimondo
authors.initials: R
authors.lastname: De Cristofaro
authors.forename: Sergio
authors.initials: S
authors.lastname: Rutella
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000002:abnormalities* / Q000201:enzymology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000201:enzymology* / Q000276:immunology*; D010950:Plasma Cells / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D047368:Tumor Burden / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D017228:Hepatocyte Growth Factor