Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan (TRP) into kynurenine (KYN), driving the development, stabilization and activation of regulatory T cells, and suppressing anti-tumor T-cell responses.We investigated IDO1 expression and function in 22 children with acute myeloid leukemia (AML; median age at diagnosis: 8 years, range 1-16). IDO expression was assessed with Western blotting; TRP and KYN levels were measured with RP-HPLC. Results: Leukemia blasts from 10 out of 21 evaluable AML cases up-regulated IDO1 expression and function after in vitro challenge with IFN-{gamma}, as indicated by higher KYN levels in supernatants of stimulated (24.3 μM/L, range 10.8-37.7) compared with unstimulated AML cells (1.3 μM/L, 0.9-2.7; p=0.0022). IDO induction was abrogated by STAT3 inhibitors; furthermore, co-immuno-precipitation assays suggested the occurrence of physical interactions between IDO and STAT3 in leukemia cells. IDO-expressing AML blasts restrained Th1 cytokine production by allogeneic CD8+ T cells, an effect that was partially abrogated by D,L-1-methyl-tryptophan, an IDO inhibitor. A Kaplan-Meier estimate of the 3-year overall survival indicated a clear benefit for IDO- AML cases compared with IDO+ ones (68% versus 33%).
Indoleamine 2,3-dioxygenase-1 (IDO1) expression by childhood acute myeloid leukemia restrains IFN-{gamma} production by T cells and may portend an unfavorable prognosis
MORETTA, Francesca;
2013-01-01
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan (TRP) into kynurenine (KYN), driving the development, stabilization and activation of regulatory T cells, and suppressing anti-tumor T-cell responses.We investigated IDO1 expression and function in 22 children with acute myeloid leukemia (AML; median age at diagnosis: 8 years, range 1-16). IDO expression was assessed with Western blotting; TRP and KYN levels were measured with RP-HPLC. Results: Leukemia blasts from 10 out of 21 evaluable AML cases up-regulated IDO1 expression and function after in vitro challenge with IFN-{gamma}, as indicated by higher KYN levels in supernatants of stimulated (24.3 μM/L, range 10.8-37.7) compared with unstimulated AML cells (1.3 μM/L, 0.9-2.7; p=0.0022). IDO induction was abrogated by STAT3 inhibitors; furthermore, co-immuno-precipitation assays suggested the occurrence of physical interactions between IDO and STAT3 in leukemia cells. IDO-expressing AML blasts restrained Th1 cytokine production by allogeneic CD8+ T cells, an effect that was partially abrogated by D,L-1-methyl-tryptophan, an IDO inhibitor. A Kaplan-Meier estimate of the 3-year overall survival indicated a clear benefit for IDO- AML cases compared with IDO+ ones (68% versus 33%).
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