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Efficacy of Levo-1-Methyl Tryptophan and Dextro-1-Methyl Tryptophan in Reversing Indoleamine-2,3-Dioxygenase–Mediated Arrest of T-Cell Proliferation in Human Epithelial Ovarian Cancer

Departments of ¹ Gynecologic Oncology, ² Immunology, ³ Pathology and Laboratory Medicine, ⁴ Surgical Pathology, ⁵ Biostatistics, and ⁶ Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, New York; ⁷ Institut National de la Santé et de la Recherche Médicale, U892, CLCC René Gauducheau, Saint Herblain, France; and ⁸ Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Kunle Odunsi, Department of Gynecologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-3497; Fax: 716-845-7608; E-mail: kunle.odunsi{at}roswellpark.org.

Key Words: 1MT • indoleamine-2,3-dioxygenase • T cell • ovarian cancer

It has been reported that levo-1-methyl tryptophan (L-1MT) can block indoleamine-2,3-dioxygenase (IDO) expressed by human dendritic cells (DC), whereas dextro-1-methyl tryptophan (D-1MT) is inefficient. However, whether L-1MT or D-1MT can efficiently reverse IDO-induced arrest of human T-cell proliferation has not been clarified. Here, we show a marked immunosuppressive effect of IDO derived from INDO-transfected 293 cell, IDO⁺ ovarian cancer cells, and monocyte-derived DCs on CD4⁺ Th1 cells, CD8⁺ T cells, and natural killer cells derived from peripheral blood, ascites, and tumors of ovarian cancer patients. We found that, whereas L-1MT and D/L-1MT can restore proliferation of tumor-derived and peripheral blood T-cell subsets, D-1MT does not effectively restore IDO-induced arrest of T-cell proliferation. Although D-1MT inhibited kynurenine production at high concentrations, L-1MT was more effective in abrogating kynurenine generation and tryptophan depletion, whereas tryptophan was completely depleted by IDO even in the presence of high amounts of D-1MT. Together, the results indicate that, whereas the generation of tryptophan metabolites (kynurenines) by IDO is important in mediating suppression of T-cell proliferation, the degree to which tryptophan depletion is restored by 1MT is also critical in overcoming IDO-induced arrest of T-cell proliferation. [Cancer Res 2009;69(13):5498–504]