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

Abstract

Doc number: 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.