Indoleamine 2,3-dioxygenase-1 (IDO1) expression by childhood acute myeloid leukemias inhibits T-cell production of IFN-γ and confers an unfavorable prognosis

  • Sergio Rutella
  • Valentina Folgiero
  • Perla Filippini
  • Valentina Bertaina
  • Riccardo Masetti
  • Marco Zecca
  • Giuseppina Li Pira
  • Giovanni F Torelli
  • Anna Maria Testi
  • Alice Bertaina
  • Andrea Pession
  • Franco Locatelli
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Keywords

Acute Myeloid Leukemia Kynurenine Acute Myeloid Leukemia Cell IDO1 Expression Acute Myeloid Leukemia Blast 
Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan into kynurenine (KYN) and other immune suppressive molecules that inhibit effector T cells and promote regulatory T-cell differentiation. We have previously shown that IDO1 mRNA and protein are detectable in blast cells from 52% of adults with newly diagnosed acute myeloid leukemia (AML). Herein, we investigated IDO1 expression and function in 41 children with AML (median age=10 years, range 1-17). In 20/41 cases, leukemia blast cells up-regulated IDO1 after in vitro challenge with IFN-γ. Of interest, microenvironmental IFN-γ was higher in IDO(pos) compared with IDO(neg) patients. In line with these results, bone marrow (BM)-resident T cells produced more IFN-γ, but not IL-4 or IL-17, compared with T cells from normal BM samples. KYN levels significantly increased in supernatants of IFN-γ-stimulated AML cells (21.0 μM/L, range 6.1-36.0) compared with unstimulated cultures (0.85 μM/L, range 0.4-1.7; p=0.0022), in parallel with tryptophan consumption (2.95 μM/L, range 1.0-37.0, after challenge with IFN-γ compared with 38.1 μM, range 18.2-50.0, in unstimulated cultures; p<0.0001). In a mixed tumor cell lymphocyte culture, AML blasts primed with IFN-γ inhibited Th1 cytokine production by allogeneic CD8+ and, to a lesser extent, CD4+ T cells, while enhancing Th2 cytokine release. The provision of D,L-1-methyl-tryptophan (1MT), an IDO inhibitor, to T-cell/AML co-cultures partially restored IFN-γ production by both CD4+ and CD8+ T cells. Furthermore, IDO-expressing AML blasts inhibited NK-cell degranulation, as measured through CD107a expression. Finally, 5-year overall survival was significantly better for IDO(neg) patients (34 months) compared with IDO(pos) ones (64.7 months; p=0.0438; Figure 1). In conclusion, IDO suppresses Th1 responses/NK activity and may portend an unfavorable prognosis in childhood AML.
Figure 1

The 5-year overall survival of IDO-positive and IDO-negative patients with AML is shown.

Copyright information

© Rutella et al; licensee BioMed Central Ltd. 2013

This article is published under license to 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.

Authors and Affiliations

  • Sergio Rutella
    • 1
  • Valentina Folgiero
    • 1
  • Perla Filippini
    • 1
  • Valentina Bertaina
    • 1
  • Riccardo Masetti
    • 2
  • Marco Zecca
    • 3
  • Giuseppina Li Pira
    • 1
  • Giovanni F Torelli
    • 4
  • Anna Maria Testi
    • 4
  • Alice Bertaina
    • 1
  • Andrea Pession
    • 2
  • Franco Locatelli
    • 1
    • 5
  1. 1.Pediatric Hematology/OncologyIRCCS Bambino Gesù Children's HospitalRomeItaly
  2. 2.Pediatric Hematology/Oncology "Lalla Seràgnoli"Univeristy of BolognaBolognaItaly
  3. 3.Pediatric Hematology/OncologyIRCCS Fondazione San MatteoPaviaItaly
  4. 4.HematologyUniversity La SapienzaRomeItaly
  5. 5.PediatricsUniversity of PaviaPaviaItaly

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