Acute Myeloid Leukemia-Derived Dendritic Cells Express the Immunoregulatory Enzyme Indoleamine 2,3-dioxygenase.

Abstract

Acute myeloid leukemia (AML) cells may be differentiated into dendritic cells (DC) which have increased immunogenicity, but retain some immunosuppressive features of leukemic cells. Indoleamine 2,3-dioxygenase (IDO) enzyme, which catalyzes the conversion of tryptophan into kynurenine, has been identified as a novel immunosuppressive agent by inhibiting T-cell proliferation and is involved in tolerance induction to tumors. We have recently shown that IDO protein is constitutively expressed in a significant subset of newly diagnosed AML patients, resulting in tryptophan catabolism along the kynurenine pathway and in the inhibition of allogeneic T-cell proliferation. We, then, in vitro generated DCs from 7 AML samples (AML-DCs) in the presence of GM-CSF, IL-4 and TNF-α. The cells we obtained were morphologically and phenotypically semi-mature DCs expressing CD40, CD80, CD86, HLA-DR and CD1a molecules and they were more efficient to induce T-cell proliferation and type 1 cytokine production than primary AML blasts. At baseline, 5/7 AML samples expressed IDO, whereas 2/7 did not. After differentiation into DCs, IDO+ AML samples showed an up-regulation of IDO mRNA and protein, and IDO− AML cells turned positive. IDO-expressing AML-DCs were capable to catabolize tryptophan into kynurenine metabolite and, functionally, they inhibited allogeneic T-cell proliferation through an IDO-dependent mechanism. These data identify IDO-mediated catabolism as a tolerogenic mechanism in AML-DCs and have clinical implications for the use of AML-DCs as cellular vaccine against leukemia.