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

Abstract

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 INDOtransfected 293 cell, IDO + ovarian cancer cells, and monocytederived 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]

Extensive Profiling of the Expression of the Indoleamine 2,3-Dioxygenase 1 Protein in Normal and Tumoral Human Tissues

“…S3B). This activity was blocked by 1-methyl-L-tryptophan, a known IDO1 inhibitor, and not by its enantiomer 1-methyl-D-tryptophan, confirming the lack of inhibition of IDO1 by the latter (37,38). When we added mature-DC conditioned medium to CD4 þ T cells activated with coated anti-CD3 antibody, we observed that T-cell proliferation was prevented, whereas it was maintained with the immature DC-conditioned medium (Supplementary Fig.…”

Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic Perspectives

“…Furthermore, IDO enzymatic activity in cancer has rarely been investigated. Interestingly, researchers in an ovarian epithelial cancer study have reported IDO expression in 43% of analyzed tissues (83/ 192), and this finding was shown to be correlated with a lower tryptophan-to-kynurenin ratio in the tumor environment (38). Similar results were obtained in a study from Huang and colleagues in which they observed that lower serum tryptophan in patients with colorectal carcinoma was correlated with reduced quality of life (39).…”

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

“…Data reported for D-1MT, a described IDO2 inhibitor currently in clinical development, indicate that there was no decrease in plasma kynurenine levels in nonhuman primates (24) or in patients in early clinical trials (27). Multiple groups have described differences between D-1MT and L-1MT, showing that it is, in fact, L-1MT that can both decrease kynurenine generation and restore impaired proliferation of several T cell subsets and that IDO1 drives tryptophan catabolism in human dendritic cells (28,29). Hydroxyamidines, active against IDO1, suppress kynurenine generation in cells and in vivo and are therefore suitable to test the hypothesis that IDO1 inhibition may provide clinical benefit to cancer patients.…”