High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome

Abstract

Indoleamine 2,3-dioxygenase degrades the amino acid tryptophan which is essential for T cells. Tryptophan depletion causes T-cell cycle arrest and solid tumors that express high levels of indoleamine 2,3-dioxygenase can create immune suppression. Recently, blasts of patients with acute myeloid leukemia were shown to express indoleamine 2,3-dioxygenase. We determined INDO (encoding gene for indoleamine 2,3-dioxygenase) mRNA expression in leukemic blasts of 286 patients with acute myeloid leukemia by gene-expression profiling. Results were validated by quantitative polymerase chain reaction analysis in blasts of an independent cohort of 71 patients. High INDO expression was correlated to significantly shortened overall and relapse-free survival. Correlation of INDO expression to relevant known prognostic factors and survival identified high INDO expression as a strong negative independent predicting variable for overall and relapse-free survival. Inhibition of indoleamine 2,3-dioxygenase expressed by myeloid leukemic blasts may result in breaking immune tolerance and offers new therapeutic options for patients with acute myeloid leukemia.

Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells

“…9 We and others have also demonstrated that acute myeloid leukemia (AML) cells express an active IDO1 protein, which converts tryptophan into kynurenine and inhibits allogeneic T-cell proliferation. [10][11][12][13] Moreover, we demonstrated that modulation of tryptophan catabolism by AML cells results in the de novo induction of Treg by conversion from CD4 + CD25 -naïve T cells. 14 AML samples have been used to generate, in vitro, DClike cells (AML-DC) which stimulate T-cell proliferation and cytotoxic T lymphocyte activity against autologous leukemia cells more efficiently than undifferentiated blasts.…”

“…In this study, we show that leukemic DC may represent another example of IDO1-expressing DC. We and others [10][11][12][13] have previously demonstrated that a subset of AML samples from newly diagnosed patients constitutively expresses significant amounts of IDO1 gene and protein. Our current results demonstrate that during DC generation IDO1 expression is markedly induced/upregulated in all AML samples.…”

A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS

“…Since blasts can have profound effects on lymphocyte number and function, we specifically evaluated differences between patients with low and high numbers of blasts in BM. 29,30 The separate analysis of the 2 groups showed statistically significantly increased frequencies of PB WT1-specific tetramer responses in patients with low but not with high blasts in BM, suggesting a potential suppressive effect of high leukemic burden on the induction of WT1-specific T-cell responses. There was, however, a significant association between mPFS and decrease in BM WT1 transcripts, suggesting that WT1, although being the target antigen, maintained its role as disease marker.…”

Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?

“…12, 59 Chamuleau et al reported that high IDO mRNA expression levels in leukemic blasts was correlated with poor disease-free survival and OS (7.4 months vs 21.4 months) in 71 patients with AML. 60 Corm et al showed that AML patients with a greater serum kynurenine/tryptophan ratio (ie, greater IDO activity) had lower survival rates. 57…”