Levo- but not dextro-1-methyl tryptophan abrogates the IDO activity of human dendritic cells

Abstract

IntroductionIDO is an enzyme that catabolizes tryptophan and was shown to protect the fetus from rejection mediated by maternal T cells. 1 Such a basic mechanism that evolved for the perpetuation of species might be expected to be used for the regulation of other biologic processes. Researchers were therefore motivated to look for a role of IDO in the regulation of immune responses in health and disease. An objective that has challenged the scientific community for decades is the unraveling of immunologic conditions that enable the development of tumors and, based on this, the design of novel therapeutic strategies for tumor prevention or treatment.Tumors are the consequence of genetic mutations leading to the expression of modified proteins. 2 Despite their potential to activate the immune response, these proteins are not capable of inducing tumor-protective immunity. Many mechanisms have been made responsible for the lack of an effective immune defense against tumors. 3 If IDO has the potential to prevent rejection of the fetus during pregnancy-so went the reasoning-it might also be implicated in induction of fatal tolerance to tumors. Tolerogenic mechanisms can operate in the tumor itself or in key sites where the immune system encounters tumor antigens, such as tumor-draining lymph nodes. 4 Emerging evidence suggests that in lymph nodes, IDO-expressing dendritic cells (DCs) directly suppress and anergize tumor-reactive effector T cells responding to antigens presented by these DCs. 5,6 In addition, through bystander suppression, IDO can inhibit T-cell responses to antigens presented by neighboring DCs. 5 It was therefore appealing to trigger antitumor immunity by inhibiting the activity of IDO. Pioneering work in this field was performed by van den Eynde and colleagues. In a series of elegant experiments, they showed that the IDO-blocking agent 1-methyltryptophan (1MT) significantly reduces the volume of tumors in preimmunized mice (Uyttenhove et al 7 ). But 1MT exists in 2 forms, the levo and the dextro isomer. In the study of van den Eynde's group the levo isoform (L-1MT) was used. Other authors found that, in animal models, the dextro stereoisomer (D-1MT) has superior antitumor activity 8 and therefore chose it for phase 1 clinical trials in humans. This was a surprising choice since, on a biochemical level, in contrast to the L isomer the D form did not properly inhibit IDO. 8 In recent studies, the contradiction was apparently resolved by describing, in addition to the classic IDO (dubbed IDO1), a closely related variant called IDO2, 9 which is strongly inhibited by D-1MT but unaffected by L-1MT. 10 Natural IDO2 was found in several tissues, including a predendritic mouse cell line. 10 Taking into consideration the potential of D-1MT for cancer therapy and the already running clinical trials, it is important to know whether in humans the effect of D-1MT can be mediated by blocking the IDO activity of DCs. We tried to find an answer to this question by studying a subset of human DCs that were claimed to ...

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

“…Selectivity for IDO1 relative to tryptophan 2, 3-dioxygenase (TDO) (EC 50 TDO: EC 50 IDO1) was 180. These efficacy and selectivity estimates for IDOInh are higher than those reported for 1-methyltryptophan (Hou et al, 2007;Lob et al, 2014), the IDO inhibitor used to-date to study effects of KYN-pathway inhibition (Dobos et al, 2012;Kiank et al, 2010;O'Connor et al, 2009b Naive mice were allocated randomly to four treatment groups: IgG2a-Vehicle (IgG2a-VEH, N=7), IgG2a-IDO inhibitor (IgG2a-IDOInh, N=8), CD40AB-VEH (N=7) and CD40AB-IDOInh (N=8).…”

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.…”

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.…”