The therapeutic potential of targeting tryptophan catabolism in cancer

Abstract

Based on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

Fig. 1

Mode of action and effects of Trp catabolism on cells in the tumour microenvironment. Effects of Trp depletion and Trp metabolites on CD8⁺ T cells, CD4⁺ T cells, myeloid cells and tumour cells are shown.

Fig. 2

Analysing IDO1 inhibitors clinical trial results. a Intra-tumoural penetrance of IDO1 inhibitors (IDO1i) could be hindered due to diminished blood supply to tumours or elevated oncotic pressure in solid tumours (left). Even if IDO1i are able to access tumours, ABC transporters can interfere with their intracellular penetrance (middle). Cellular uptake of IDO1i can lead to AHR activation in various cell types and therefore contribute to cancer progression (right). b Combination of IDOi with other types of therapies can lead to the upregulation of IDO1 expression through various mechanisms (see text). In addition, clinical trials have included patients pre-treated with BRAF inhibitors (BRAFi), which were shown to promote an enrichment of a population of cells with constitutive AHR activity. This might further lead to the induction of IDO1 expression and contribute  to  cancer progression. c Even if IDO1 inhibition is effectively achieved, IDO2 and TDO2 might compensate for IDO1 blockade. BRAFi and IDO1i can promote AHR activation in various cells present in the tumour microenvironment, which unleashes the intrinsic cancer promoting effects driven by the AHR. Moreover, AHR activation leads to the upregulation of IDO2 and TDO2, which can further activate the AHR and deplete Trp. IDO1i and immune check point blockade (ICB) lead to an increase in cytotoxic TILs, which in turn secrete pro-inflammatory molecules, such as IFN-γ, which also induces IDO2. In addition, the pro-inflammatory microenvironment driven by IDO1i and ICB therapy can also lead to the upregulation of TDO2, via the COX2–PGE₂–EP4 pathway. d In order to obtain a more robust view of the effects of IDO1 inhibition and improve the outcome of its use in clinical trials, we suggest stratifying patients based on the concentration of Trp, Kyn and Kyn-derived metabolites in plasma and tumours, as well as on the expression of the TCE and AHR activity present in tumours. Once stratified, patients can be treated more accurately with one or more therapies targeting Trp catabolism.

Fig. 3

Analytical approaches for quantification expression and activity of tryptophan catabolising enzymes (TCEs) in cancer therapies. The levels of Trp and its metabolites can be measured by chromatographic methods, including high-performance liquid chromatography (HPLC), gas chromatography–mass spectrometry (GC-MS) or liquid chromatography–mass spectrometry (LC-MS). Antibodies detecting Trp, as well as specific metabolites of the Trp degradation pathway, enable enzyme-linked immunosorbent assay (ELISA) measurements.^,– Furthermore, matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS) imaging allows visualisation of Trp and Kyn in tissue,^, while position-emission tomography (PET) imaging with Trp-derived tracers enables visualisation of Trp uptake in vivo.^– In addition, TCE expression can be detected on mRNA and protein levels, however care must be taken when selecting anti-IDO1 antibodies, as many lack selectivity, particularly for immunohistochemistry. The blue area of the circle illustrates methods used for measuring Trp and its metabolites; the yellow area illustrates methods used for detcting the expression of TCE and AHR activity. IF: immunofluorescence; WB: Western blot. PET-imaging example was reproduced under a Creative Commons CC-BY license from. RNA-seq example was reproduced under a Creative Commons CC-BY license from. Western Blot example was provided by the authors.