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

Autor: Franco Locatelli, Alberto Rocci, Valentina Folgiero, Antonio Palumbo, Giuseppina Bonanno, Manuela Gambella, Raimondo De Cristofaro, Sergio Rutella, Linda Novarese, Giovanni Scambia, Andrea Mariotti, Marilena Ciciarello, Annabella Procoli, Luca De Rosa, Daniela Natale, Ignazio Majolino
Přispěvatelé: 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
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Cellular differentiation
T-Lymphocytes
lcsh:Medicine
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
Plasma cell
chemistry.chemical_compound
IDO1
Indoleamine 2
3-dioxygenase
Multiple myeloma
Medicine(all)
Tumor
General Medicine
Regulatory
Interleukin 10
medicine.anatomical_structure
Indoleamine
Biology
Indoleamine-Pyrrole 2
General Biochemistry
Genetics and Molecular Biology
Cell Line
Immune system
Antigen
medicine
Antigens
Biochemistry
Genetics and Molecular Biology(all)
Research
Settore MED/09 - MEDICINA INTERNA
lcsh:R
medicine.disease
Settore MED/40 - GINECOLOGIA E OSTETRICIA
chemistry
Immunology
Dioxygenase
Neoplasm
Kynurenine
Zdroj: Journal of Translational Medicine, Vol 10, Iss 1, p 247 (2012)
Journal of Translational Medicine
ISSN: 1479-5876
Popis: 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.
Databáze: OpenAIRE
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