Leukemic Transformation Induces the Constitutive Expression of Indoleamine 2,3-Dyoxigenase Which Directly Increases CD4⁺CD25⁺ T Regulatory Cells.

The expression of the catalytic enzyme of tryptophan, indoleamine 2,3-dyoxigenase (IDO) in different cellular subsets, including solid tumors, has been recently identified as a T-cell inhibitory effector pathway. Here, we show that unlikely normal hematopoietic CD34⁺ cells expressing IDO only upon stimulation with IFN-γ, acute myeloid leukemia (AML) cells constitutively express IDO and inhibit allogeneic T-cell proliferation. IDO expression correlates with increased CD4⁺CD25⁺Foxp3⁺ T cells in AML patients at diagnosis. In vitro, IDO⁺ AML cells increase the percentage and the absolute number of CD4⁺CD25^bright T cells, also expressing surface CTLA-4 and Foxp3 mRNA. The addition of the IDO-inhibitor, 1-methyl tryptophan (1-MT), completely abrogates such increase. Purified CD4⁺CD25⁺ T cells obtained from coculture with IDO⁺ AML cells are not proliferating and unable to produce IL-2. They also inhibit naive T-cell proliferation and Th1 skewing. Co-culture with IDO⁺ AML cells results in the conversion of CD4⁺CD25⁻ into CD4⁺CD25⁺ T cells and the addition of 1-MT completely abrogates this effect. In mice, intrasplenic injection of IDO-expressing leukemia/lymphoma A20 cells induces the increase of CD4⁺CD25⁺ T cells, which can be blocked by 1-MT treatment. These data suggest that AML cells have the capacity to directly increase a population of T regulatory cells through the constitutive expression of the functionally active form of IDO. IDO expression can be regarded as a novel mechanism of leukemia escape from immune control and its inhibition may represent a novel anti-leukemia therapeutic strategy.