Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M et al.. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67: 792-801

Immunotherapy Center and Departments of Pediatrics, Medicine, and Biostatistics, Medical College of Georgia, Augusta, Georgia.
Cancer Research (Impact Factor: 9.33). 02/2007; 67(2):792-801. DOI: 10.1158/0008-5472.CAN-06-2925
Source: PubMed


Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that contributes to tolerance in a number of biological settings. In cancer, IDO activity may help promote acquired tolerance to tumor antigens. The IDO inhibitor 1-methyl-tryptophan is being developed for clinical trials. However, 1-methyl-tryptophan exists in two stereoisomers with potentially different biological properties, and it has been unclear which isomer might be preferable for initial development. In this study, we provide evidence that the D and L stereoisomers exhibit important cell type-specific variations in activity. The L isomer was the more potent inhibitor of IDO activity using the purified enzyme and in HeLa cell-based assays. However, the D isomer was significantly more effective in reversing the suppression of T cells created by IDO-expressing dendritic cells, using both human monocyte-derived dendritic cells and murine dendritic cells isolated directly from tumor-draining lymph nodes. In vivo, the d isomer was more efficacious as an anticancer agent in chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer. The D isomer of 1-methyl-tryptophan specifically targeted the IDO gene because the antitumor effect of D-1-methyl-tryptophan was completely lost in mice with a disruption of the IDO gene (IDO-knockout mice). Taken together, our findings support the suitability of D-1-methyl-tryptophan for human trials aiming to assess the utility of IDO inhibition to block host-mediated immunosuppression and enhance antitumor immunity in the setting of combined chemo-immunotherapy regimens.

Download full-text


Available from: Andrew L Mellor, Oct 03, 2015
106 Reads
  • Source
    • "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). Using a single IDOInh dose of 200 mg/kg p.o., the time required to reach peak plasma exposure was 1.3 h, and the mean residence time (average time that an IDOInh molecule remains in the blood) was 4.6 h. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 07/2015; DOI:10.1016/j.bbi.2015.06.184 · 5.89 Impact Factor
  • Source
    • "We have recently developed TRP metabolism measures, using tandem mass spectrometry coupled with liquid chromatography in our laboratory. This approach may lead to therapeutic options, as some authors have viewed IDO or TDO inhibitors as a potential anticancer therapy [77] [118]. However, other potential targets in TRP metabolism need to be explored. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Obstructive sleep apnea (OSA) is a multi-component chronic disease affecting 6-17% of adults in the general population. The main hallmark of OSA, intermittent hypoxia (IH), is reported as the main trigger for cardiometabolic co-morbidities. Recent studies, both in rodent models exposed to IH and in humans, have suggested an enhanced incidence and accelerated progression of cancer. However, mechanisms underlying the relationships between OSA and cardiovascular disease on one hand, and cancer on the other hand, have not been entirely deciphered yet. Tryptophan (TRP) metabolism results in nicotinamid and serotonin production, but also in the production of numerous intermediates such as kynurenine, anthranilic and kynurenic acids, 3-hydroxykynurenine, 3-hydroxyanthranilic and quinolinic acids. Each of these metabolites has been linked to cardiovascular disease and cancer mainly in epidemiologic studies. We hypothesize that an alteration of TRP metabolism may play a role in OSA-related cardiovascular co-morbidities and might be one of the players in the relationship between cancer and intermittent hypoxia/OSA. If this is true, interventions aiming to modify TRP metabolism, may constitute a new therapeutic strategy against cardiovascular disease progression and cancer occurrence in OSA populations. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Medical Hypotheses 07/2015; DOI:10.1016/j.mehy.2015.06.022 · 1.07 Impact Factor
  • Source
    • "In preclinical models, IDO-inhibitors were shown to have synergistic effects when administered with multiple classes of chemotherapy agents and radiation [14,15]. Early-phase clinical trials combining standard chemotherapy with IDO-inhibitor drugs, such as 1-methyl-D-tryptophan (D-1MT, indoximod) and NLG919, for treatment of refractory solid tumors are in progress. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent complement deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and complement-dependent tumor destruction. Methods To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy. Results Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread complement deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no complement deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread deposition of complement. Mice genetically deficient in complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival. Conclusions Together these findings identify a novel mechanistic link between IDO and complement, and implicate complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.
    07/2014; 2(1). DOI:10.1186/2051-1426-2-21
Show more