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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: 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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Text
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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: |
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| 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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