Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface

Abstract

The mechanisms underlying a relationship between inflammation and cancer are unclear, but much emphasis has been placed on the role of tryptophan metabolism to kynurenine and downstream metabolites, as these make a substantial contribution to the regulation of immune tolerance and susceptibility to cancer. The proposed link is supported by the induction of tryptophan metabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), in response to injury, infection or stress. This review will summarize the kynurenine pathway and will then focus on the bi-directional interactions with other transduction pathways and cancer-related factors. The kynurenine pathway can interact with and modify activity in many other transduction systems, potentially generating an extended web of effects other than the direct effects of kynurenine and its metabolites. Conversely, the pharmacological targeting of those other systems could greatly enhance the efficacy of changes in the kynurenine pathway. Indeed, manipulating those interacting pathways could affect inflammatory status and tumor development indirectly via the kynurenine pathway, while pharmacological modulation of the kynurenine pathway could indirectly influence anti-cancer protection. While current efforts are progressing to account for the failure of selective IDO1 inhibitors to inhibit tumor growth and to devise means of circumventing the issue, it is clear that there are wider factors involving the relationship between kynurenines and cancer that merit detailed consideration as alternative drug targets.

Regulation of a Metabolic Gene Signature in Response to Respiratory Viruses and Type I Interferon Signaling

“…Furthermore, a protein interaction analysis using the STRING database revealed strong interactions between unfolded protein response (UPR) and IDO1-regulated proteins that were activated specifically in response to SARS-CoV-2 infection as well as with transcription factors of the antiviral subnetwork and the metabolic gene signature to form a gene regulatory network or GRN (Figure 10). These results indicate that IDO1 is a critical regulator at the intersection of metabolism, inflammation, and cancer [67].…”

Persistent tailoring of MSC activation through genetic priming

“…IDO1 exerts immunomodulatory effects by converting tryptophan into kynurenine within the tryptophan metabolic pathway. 41 Kynurenine levels were also elevated using both priming techniques and were indistinguishable between MSC IRF1 and MSC IFNγ (p = 0.63; Figure 1E). Together these results demonstrate that IRF1 transgene expression in MSCs can recapitulate key activation signatures of IFNγ stimulation.…”

Lipid Peroxidation-Related Redox Signaling in Osteosarcoma

“…A high expression of IDO is associated with a poor prognosis and metastasis in OS patients [175]. In addition, the expression of IDO and programmed death ligand 1 (PD-1) is higher in OS who have received neoadjuvant chemotherapy, suggesting an adaptive mechanism to therapy [176,177].…”