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

Curti, A, Trabanelli, S, Onofri, C, Aluigi, M, Salvestrini, V, Ocadlikova, D, Evangelisti, C, Rutella, S ORCID: 0000-0003-1970-7375, De Cristofaro, R, Ottaviani, E, Baccarani, M and Lemoli, RM, 2010. Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells. Haematologica, 95 (12), pp. 2022-2030. ISSN 0390-6078

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Background: The immunoregulatory enzyme indoleamine 2,3-dioxygenase, which catalyzes the conversion of tryptophan into kynurenine, is expressed in a significant subset of patients with acute myeloid leukemia, resulting in the inhibition of T-cell proliferation and the induction of regulatory T cells. Acute myeloid leukemia cells can be differentiated into dendritic cells, which have increased immunogenicity and have been proposed as vaccines against leukemia.
Design and Methods: Leukemic dendritic cells were generated from acute myeloid leukemia cells and used as stimulators in functional assays, including the induction of regulatory T cells. Indoleamine 2,3-dioxygenase expression in leukemic dendritic cells was evaluated at molecular, protein and enzymatic levels.
Results: We demonstrate that, after differentiation into dendritic cells, both indoleamine 2,3-dioxygenase-negative and indoleamine 2,3-dioxygenase-positive acute myeloid leukemia samples show induction and up-regulation of indoleamine 2,3-dioxygenase gene and protein, respectively. Indoleamine 2,3-dioxygenase-positive acute myeloid leukemia dendritic cells catabolize tryptophan into kynurenine metabolite and inhibit T-cell proliferation through an indoleamine 2,3-dioxygenase-dependent mechanism. Moreover, indoleamine 2,3-dioxygenase-positive leukemic dendritic cells increase the number of allogeneic and autologous CD4+CD25+ Foxp3+ T cells and this effect is completely abrogated by the indoleamine 2,3-dioxygenase-inhibitor, 1-methyl tryptophan. Purified CD4+CD25+ T cells obtained from co-culture with indoleamine 2,3-dioxygenase-positive leukemic dendritic cells act as regulatory T cells as they inhibit naive T-cell proliferation and impair the complete maturation of normal dendritic cells. Importantly, leukemic dendritic cell-induced regulatory T cells are capable of in vitro suppression of a leukemia-specific T cell-mediated immune response, directed against the leukemia-associated antigen, Wilms’ tumor protein.
Conclusions: These data identify indoleamine 2,3-dioxygenase-mediated catabolism as a tolerogenic mechanism exerted by leukemic dendritic cells and have clinical implications for the use of these cells for active immunotherapy of leukemia.

Item Type: Journal article
Publication Title: Haematologica
Creators: Curti, A., Trabanelli, S., Onofri, C., Aluigi, M., Salvestrini, V., Ocadlikova, D., Evangelisti, C., Rutella, S., De Cristofaro, R., Ottaviani, E., Baccarani, M. and Lemoli, R.M.
Publisher: Ferrata Storti Foundation
Date: December 2010
Volume: 95
Number: 12
ISSN: 0390-6078
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 13 Sep 2016 13:33
Last Modified: 09 Jun 2017 14:05

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