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

Antonio Curti, Sara Trabanelli, Chiara Onofri, Michela Aluigi, Valentina Salvestrini, Darina Ocadlikova, Cecilia Evangelisti, Sergio Rutella, Raimondo de Cristofaro, Emanuela Ottaviani, Michele Baccarani, Roberto M. Lemoli

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2022-2030
Number of pages9
JournalHaematologica
Volume95
Issue number12
DOIs
Publication statusPublished - Dec 2010

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Regulatory T-Lymphocytes
Dendritic Cells
Leukemia
Acute Myeloid Leukemia
T-Lymphocytes
Kynurenine
Cell Proliferation
Myeloid Cells
Tryptophan
T-Cell Leukemia
Active Immunotherapy
Proteins
Wilms Tumor
Coculture Techniques
Up-Regulation
Vaccines
Cell Count

Keywords

  • 3-dioxygenase
  • Acute myeloid leukemia
  • Dendritic cells
  • Immunotherapy
  • Indoleamine 2
  • T regulatory cells

ASJC Scopus subject areas

  • Hematology

Cite this

Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells. / Curti, Antonio; Trabanelli, Sara; Onofri, Chiara; Aluigi, Michela; Salvestrini, Valentina; Ocadlikova, Darina; Evangelisti, Cecilia; Rutella, Sergio; de Cristofaro, Raimondo; Ottaviani, Emanuela; Baccarani, Michele; Lemoli, Roberto M.

In: Haematologica, Vol. 95, No. 12, 12.2010, p. 2022-2030.

Research output: Contribution to journalArticle

Curti, A, Trabanelli, S, Onofri, C, Aluigi, M, Salvestrini, V, Ocadlikova, D, Evangelisti, C, Rutella, S, de Cristofaro, R, Ottaviani, E, Baccarani, M & Lemoli, RM 2010, 'Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells', Haematologica, vol. 95, no. 12, pp. 2022-2030. https://doi.org/10.3324/haematol.2010.025924
Curti, Antonio ; Trabanelli, Sara ; Onofri, Chiara ; Aluigi, Michela ; Salvestrini, Valentina ; Ocadlikova, Darina ; Evangelisti, Cecilia ; Rutella, Sergio ; de Cristofaro, Raimondo ; Ottaviani, Emanuela ; Baccarani, Michele ; Lemoli, Roberto M. / Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells. In: Haematologica. 2010 ; Vol. 95, No. 12. pp. 2022-2030.
@article{27b2b656f8bd4938b6727d0ef5ea9b17,
title = "Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells",
abstract = "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.",
keywords = "3-dioxygenase, Acute myeloid leukemia, Dendritic cells, Immunotherapy, Indoleamine 2, T regulatory cells",
author = "Antonio Curti and Sara Trabanelli and Chiara Onofri and Michela Aluigi and Valentina Salvestrini and Darina Ocadlikova and Cecilia Evangelisti and Sergio Rutella and {de Cristofaro}, Raimondo and Emanuela Ottaviani and Michele Baccarani and Lemoli, {Roberto M.}",
year = "2010",
month = "12",
doi = "10.3324/haematol.2010.025924",
language = "English",
volume = "95",
pages = "2022--2030",
journal = "Haematologica",
issn = "0390-6078",
publisher = "NLM (Medline)",
number = "12",

}

TY - JOUR

T1 - Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells

AU - Curti, Antonio

AU - Trabanelli, Sara

AU - Onofri, Chiara

AU - Aluigi, Michela

AU - Salvestrini, Valentina

AU - Ocadlikova, Darina

AU - Evangelisti, Cecilia

AU - Rutella, Sergio

AU - de Cristofaro, Raimondo

AU - Ottaviani, Emanuela

AU - Baccarani, Michele

AU - Lemoli, Roberto M.

PY - 2010/12

Y1 - 2010/12

N2 - 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.

AB - 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.

KW - 3-dioxygenase

KW - Acute myeloid leukemia

KW - Dendritic cells

KW - Immunotherapy

KW - Indoleamine 2

KW - T regulatory cells

UR - http://www.scopus.com/inward/record.url?scp=78649901580&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649901580&partnerID=8YFLogxK

U2 - 10.3324/haematol.2010.025924

DO - 10.3324/haematol.2010.025924

M3 - Article

C2 - 20801903

AN - SCOPUS:78649901580

VL - 95

SP - 2022

EP - 2030

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 12

ER -