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Indoleamine 2,3-dioxygenase-1 (IDO1) expression by childhood acute myeloid leukemias inhibits T-cell production of IFN-γ and confers an unfavorable prognosis
  1. Sergio Rutella1,
  2. Valentina Folgiero1,
  3. Perla Filippini1,
  4. Valentina Bertaina1,
  5. Riccardo Masetti2,
  6. Marco Zecca3,
  7. Giuseppina Li Pira1,
  8. Giovanni F Torelli4,
  9. Anna Maria Testi4,
  10. Alice Bertaina1,
  11. Andrea Pession2 and
  12. Franco Locatelli1,5
  1. Aff1 grid.414125.70000000107276809Pediatric Hematology/OncologyIRCCS Bambino Gesù Children's Hospital Rome Italy
  2. Aff2 grid.6292.f0000000417571758Pediatric Hematology/Oncology "Lalla Seràgnoli"Univeristy of Bologna Bologna Italy
  3. Aff3 Pediatric Hematology/OncologyIRCCS Fondazione San Matteo Pavia Italy
  4. Aff4 grid.7841.aHematologyUniversity La Sapienza Rome Italy
  5. Aff5 grid.8982.b0000000417625736PediatricsUniversity of Pavia Pavia Italy

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Meeting abstracts

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.