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.

Keywords: IDO1; IDO2; TDO; indoleamine-2,3-dioxygenase; kynurenic acid; kynurenine.

Figure 1

A summary of the major components of the kynurenine pathway and the enzymes responsible for their metabolism.

Figure 2

A diagram of the major cellular sites of production, uptake and actions of compounds in the kynurenine pathway and their effects in the immune system relevant to carcinogenesis. Positive signs indicate activation or enhancement, while negative signs indicate inhibition or suppression.

Figure 3

Structures of tryptophan and its major kynurenine pathway metabolites, with examples of the IDO1 inhibitors mentioned in the text.

Figure 4

Sites of action and interactions of IDO, TDO, IL4i1 and their products of tryptophan metabolism (yellow shading) with a variety of other transduction systems cited in the text. The examples shown are not specific for any cell type, though all are relevant, directly or indirectly, to the formation or removal of tumors.