Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma

Giovanni Scambia, Raimondo De Cristofaro, Giuseppina Bonanno, Annabella Procoli, Daniela Natale, Linda Novarese, Sergio Rutella, Valentina Folgiero, Luca De Rosa, Ignazio Majolino, Alberto Rocci, Manuela Gambella, Marilena Ciciarello, Antonio Palumbo, Franco Locatelli

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)247-264
Number of pages18
JournalJournal of Translational Medicine
Volume10
DOIs
Publication statusPublished - 2012

Keywords

  • Antigens, Neoplasm
  • CD8-Positive T-Lymphocytes
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Hepatocyte Growth Factor
  • Humans
  • Immune System
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-10
  • Membrane Proteins
  • Multiple Myeloma
  • Plasma Cells
  • STAT3 Transcription Factor
  • Signal Transduction
  • T-Lymphocytes, Regulatory
  • Transforming Growth Factor beta
  • Tumor Burden

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