| Summary: | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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<sup>+</sup> T cells.</p> <p>Results</p> <p>KYN was increased in 75% of patients with symptomatic MM and correlated with the expansion of CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> Treg cells and the contraction of NY-ESO-1-specific CD8<sup>+</sup> T cells. <it>In vitro</it>, primary MM cells promoted the differentiation of allogeneic CD4<sup>+</sup> T cells into <it>bona fide</it> CD4<sup>+</sup>CD25<sup>hi</sup>FoxP3<sup>hi</sup> 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 <smcaps>d,l</smcaps>-1-methyl-tryptophan, a chemical inhibitor of IDO. Notably, HGF levels were higher within the BM microenvironment of patients with IDO<sup>+</sup> myeloma disease compared with patients having IDO<sup>-</sup> 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.</p> <p>Conclusions</p> <p>These data suggest that IDO1 expression may contribute to immune suppression in patients with MM and possibly other HGF-producing cancers.</p>
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