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

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

Research output: Contribution to journalArticle

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+CD25hiFoxP3hi 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
Article number247
JournalJournal of Translational Medicine
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 11 2012

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Immune system
Multiple Myeloma
T-cells
Immune System
Hepatocyte Growth Factor
Kynurenine
Regulatory T-Lymphocytes
Tryptophan
T-Lymphocytes
Proto-Oncogene Proteins c-met
Phosphorylation
Cell Differentiation
Interleukin-4
Interleukin-10
Interleukin-2
Paraproteinemias
Plasmas
Plasma Cells
Neoplasms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. / Bonanno, Giuseppina; Mariotti, Andrea; Procoli, Annabella; Folgiero, Valentina; Natale, Daniela; De Rosa, Luca; Majolino, Ignazio; Novarese, Linda; Rocci, Alberto; Gambella, Manuela; Ciciarello, Marilena; Scambia, Giovanni; Palumbo, Antonio; Locatelli, Franco; De Cristofaro, Raimondo; Rutella, Sergio.

In: Journal of Translational Medicine, Vol. 10, No. 1, 247, 11.12.2012.

Research output: Contribution to journalArticle

Bonanno, G, Mariotti, A, Procoli, A, Folgiero, V, Natale, D, De Rosa, L, Majolino, I, Novarese, L, Rocci, A, Gambella, M, Ciciarello, M, Scambia, G, Palumbo, A, Locatelli, F, De Cristofaro, R & Rutella, S 2012, 'Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma', Journal of Translational Medicine, vol. 10, no. 1, 247. https://doi.org/10.1186/1479-5876-10-247
Bonanno, Giuseppina ; Mariotti, Andrea ; Procoli, Annabella ; Folgiero, Valentina ; Natale, Daniela ; De Rosa, Luca ; Majolino, Ignazio ; Novarese, Linda ; Rocci, Alberto ; Gambella, Manuela ; Ciciarello, Marilena ; Scambia, Giovanni ; Palumbo, Antonio ; Locatelli, Franco ; De Cristofaro, Raimondo ; Rutella, Sergio. / Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. In: Journal of Translational Medicine. 2012 ; Vol. 10, No. 1.
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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+CD25hiFoxP3hi 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.",
author = "Giuseppina Bonanno and Andrea Mariotti and Annabella Procoli and Valentina Folgiero and Daniela Natale and {De Rosa}, Luca and Ignazio Majolino and Linda Novarese and Alberto Rocci and Manuela Gambella and Marilena Ciciarello and Giovanni Scambia and Antonio Palumbo and Franco Locatelli and {De Cristofaro}, Raimondo and Sergio Rutella",
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T1 - Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma

AU - Bonanno, Giuseppina

AU - Mariotti, Andrea

AU - Procoli, Annabella

AU - Folgiero, Valentina

AU - Natale, Daniela

AU - De Rosa, Luca

AU - Majolino, Ignazio

AU - Novarese, Linda

AU - Rocci, Alberto

AU - Gambella, Manuela

AU - Ciciarello, Marilena

AU - Scambia, Giovanni

AU - Palumbo, Antonio

AU - Locatelli, Franco

AU - De Cristofaro, Raimondo

AU - Rutella, Sergio

PY - 2012/12/11

Y1 - 2012/12/11

N2 - 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+CD25hiFoxP3hi 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.

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