Expression of indoleamine 2,3-dioxygenase (IDO) in multiple myeloma promotes the generation of regulatory T cells: Investigations into the role of hepatocyte growth factor (40.1)

Abstract

Abstract Multiple myeloma (MM) is a plasma cell (PC) malignancy with a unique ability to evade immunosurveillance through the induction of APC dysfunction and the expansion of regulatory T cells (Treg). Hepatocyte growth factor (HGF) is elevated in MM and confers an unfavorable prognosis. We have previously shown that HGF induces the tryptophan (Trp)-degrading enzyme indoleamine 2,3-dioxygenase (IDO) in human monocytes. In this study, IDO-1 was detected in OPM-2, MOLP-8 and LP-1 MM cell lines but not in HUNS-1 cells. Kynurenine (KYN) production and Trp depletion were evidenced in supernatants of IDO-1+ MM cells, suggesting that IDO-1 may be functional. When challenged with exogenous HGF, IDO- HUNS-1 cells up-regulated IDO-1 mRNA 6-fold on average. IDO-1+ MM cells promoted the conversion of allogeneic CD4+CD25- T cells into bona fide CD4+FoxP3+ Tregs. We also detected IDO-1 expression in 6 out of 10 PC samples from patients with MM. Higher percentages of CD4+FoxP3+ Tregs were measured in IDO-1+ compared with IDO-1- MM. Intriguingly, serum KYN levels were higher in IDO-1+ compared with IDO-1- MM, suggesting that IDO-1 may mediate the in vivo expansion of Tregs through immunosuppressive KYN. Finally, serum HGF was over-represented in IDO-1+ compared with IDO-1- MM, providing indirect clues in favor of in vivo HGF effects on IDO-1 expression. Collectively, these data point to HGF as a potential inducer of IDO-1 in MM. Whether this will impact on the ability of the immune system to control disease progression remains to be prospectively investigated in larger cohorts of patients.