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

Bonanno, G, Mariotti, A, Procoli, A, Folgiero, V, Natale, D, De Rosa, L, Majolino, I, Novarese, L, Rocci, A, Gambella, M, Ciciarello, M, Scambia, G, Palumbo, A, Locatelli, F, De Cristofaro, R and Rutella, S ORCID: https://orcid.org/0000-0003-1970-7375, 2012. Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. Journal of Translational Medicine, 10, p. 247. ISSN 1479-5876

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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+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.

Item Type:	Journal article
Publication Title:	Journal of Translational Medicine
Creators:	Bonanno, G., Mariotti, A., Procoli, A., Folgiero, V., Natale, D., De Rosa, L., Majolino, I., Novarese, L., Rocci, A., Gambella, M., Ciciarello, M., Scambia, G., Palumbo, A., Locatelli, F., De Cristofaro, R. and Rutella, S.
Publisher:	BioMed Central
Date:	11 December 2012
Volume:	10
ISSN:	1479-5876
Identifiers:	Number Type 10.1186/1479-5876-10-247 DOI
Rights:	© 2012 Bonanno et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Jill Tomkinson
Date Added:	13 Sep 2016 09:56
Last Modified:	13 Oct 2017 10:58
URI:	https://irep.ntu.ac.uk/id/eprint/28476

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