Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase

Uyttenhove, Catherine; Pilotte, Luc; Théate, Ivan; Stroobant, Vincent; Colau, Didier; Parmentier, Nicolas; Boon, Thierry; Eynde, Benoı̂t J. Van den

doi:10.1038/nm934

Cited by 2,061 publications

(1,875 citation statements)

References 35 publications

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“…10 Since its first characterization as a competitive inhibitor of IDO, 37 1-MT has become the compound of reference for IDO-blocking studies. 21,22,[38][39][40] Its ability to block IDO activation in response to LPS is demonstrated in the present study by the decreased kynurenine/ tryptophan ratio that is observed in both the periphery and the brain of 1-MT-treated mice. Since the main consequence of IDO activation is development of immunotolerance because of an inability of tryptophan-deprived T cells to proliferate and induce cytotoxicity, blockade of IDO has mainly been studied in the context of reproductive physiology and tumor immune surveillance.…”

Section: Discussionsupporting

confidence: 58%

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

O’Connor

Lawson²,

André³

et al. 2008

Mol Psychiatry

1,121

992

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Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.

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Section: Discussionsupporting

confidence: 58%

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

O’Connor

Lawson²,

André³

et al. 2008

Mol Psychiatry

1,121

992

View full text Add to dashboard Cite

show abstract

“…To explore if a relationship exists between the expression of TDO2 and the two TrpRS, we selected glioma, breast cancer, and ovarian carcinoma as cancer entities, which are known to express high TDO2 levels 15-17 . Indeed TDO2 expression correlated with WARS but not WARS2 (Figure 2A and B), although the correlations were less strong than for IDO1 (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, the question arises whether the accumulation of Trp metabolites or the depletion of Trp induces WARS. To this end we cultured A172 glioblastoma cells, which exhibit constitutive TDO2 activity 16,17 , for 5 days in complete medium without or with additional Trp supplementation. Trp supplementation, a condition that promotes the accumulation of Trp metabolites, reduced WARS expression (Figure 3A), while not affecting WARS2 (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“…IDO1, for instance, is expressed in about 58% of human cancers 14 , and also TDO2 is present in multiple cancer entities including melanoma, ovarian carcinoma, hepatic carcinoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, breast cancer and glioblastoma 15–17 . As the degradation of the essential amino acid Trp is a key mechanism for immune evasion in many tumors, the question arises how the tumor cells concomitantly sustain their capacity for protein synthesis and excessive proliferation.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

et al. 2018

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Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases. As the tryptophanyl-tRNA synthestases compete for Trp with the Trp-catabolizing enzymes, the balance between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2) was positively associated with the expression of the tryptophanyl-tRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified in this study is their joint induction by IFNγ released from tumor-infiltrating T cells. Moreover, we show here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and induction of activating transcription factor 4 (ATF4). Trp deprivation induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2 protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the upregulation of WARS via IFNγ and/or GCN2-peIF2α-ATF4 signaling protects Trp-degrading cancer cells from excessive intracellular Trp depletion.

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“…T cell suppression by systemic CpG-ODN treatment is mediated by IDO activity For investigation of the functional relevance of IDO expression, the tryptophan analogue 1-methyl-tryptophan (1-MT), a well-established competitive inhibitor of IDO [19,20,22], was used. OVA-induced proliferation of CFSE-labeled OT-I cells was blocked by the presence of CpG-ODN in in vitro culture (Fig.…”

Section: Cpg-odn Treatment Impairs Antigen-specific Clonal T Cell Expmentioning

confidence: 99%

Systemic application of CpG‐rich DNA suppresses adaptive T cell immunity via induction of IDO

et al. 2005

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CpG-rich oligonucleotides (CpG-ODN) bind to Toll-like receptor 9 (TLR9) and are used as powerful adjuvants for vaccination. Here we report that CpG-ODN not only act as immune stimulatory agents but can also induce strong immune suppression depending on the anatomical location of application. In agreement with the adjuvant effect, subcutaneous application of antigen plus CpG-ODN resulted in antigen-specific T cell activation in local lymph nodes. In contrast, systemic application of CpG-ODN resulted in suppression of T cell expansion and CTL activity in the spleen. The suppressive effect was mediated by indoleamine 2,3-dioxygenase (IDO) as indicated by the observation that CpG-ODN induced IDO in the spleen and that T cell suppression could be abrogated by 1-methyl-tryptophan (1-MT), an inhibitor of IDO. No expression of IDO was observed in lymph nodes after injection of CpG-ODN, explaining why suppression was restricted to the spleen. Studies with a set of knockout mice demonstrated that the CpG-ODN-induced immune suppression is dependent on TLR9 stimulation and independent of type I and type II interferons. The present study shows that for the use of CpG-ODN as an adjuvant in vaccines, the route of application is crucial and needs to be considered. In addition, the results indicate that down-modulation of immune responses by CpG-ODN may be possible in certain pathological conditions. See accompanying commentary: http://dx

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Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase

Cited by 2,061 publications

References 35 publications

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

Systemic application of CpG‐rich DNA suppresses adaptive T cell immunity via induction of IDO

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