Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma.
J Transl Med
; 10: 247, 2012 Dec 11.
Article
en En
| MEDLINE
| ID: mdl-23232072
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Indolamina-Pirrol 2,3,-Dioxigenasa
/
Sistema Inmunológico
/
Mieloma Múltiple
Límite:
Humans
Idioma:
En
Revista:
J Transl Med
Año:
2012
Tipo del documento:
Article
País de afiliación:
Italia