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

J Transl Med. 2012 Dec 11;10:247. doi: 10.1186/1479-5876-10-247.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antigens, Neoplasm
  • CTAG1B protein, human
  • IDO1 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Membrane Proteins
  • STAT3 Transcription Factor
  • Transforming Growth Factor beta
  • Interleukin-10
  • Hepatocyte Growth Factor