Tryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO

Abstract

Blockade of the immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) holds enormous promise for sensitising cancer patients to immune checkpoint blockade. Yet, only IDO1 inhibitors had entered clinical trials so far, and those agents have generated disappointing clinical results. Improved understanding of molecular mechanisms involved in the immune-regulatory function of the tryptophan catabolism is likely to optimise therapeutic strategies to block this pathway. The immunosuppressive role of tryptophan metabolite kynurenine is becoming increasingly clear, but it remains a mystery if tryptophan exerts functions beyond serving as a precursor for kynurenine. Here we hypothesise that tryptophan acts as a rheostat of kynurenine-mediated immunosuppression by competing with kynurenine for entry into immune T-cells through the amino acid transporter called System L. This hypothesis stems from the observations that elevated tryptophan levels in TDO-knockout mice relieve immunosuppression instigated by IDO1, and that the vacancy of System L transporter modulates kynurenine entry into CD4+ T-cells. This hypothesis has two potential therapeutic implications. Firstly, potent TDO inhibitors are expected to indirectly inhibit IDO1 hence development of TDO-selective inhibitors appears advantageous compared to IDO1-selective and dual IDO1/TDO inhibitors. Secondly, oral supplementation with System L substrates such as leucine represents a novel potential therapeutic modality to restrain the immunosuppressive kynurenine and restore anti-tumour immunity.

Keywords: AhR; IDO1; System L; TDO; immunotherapy; inhibitors; kynurenine; tryptophan.

Figure 1

The immunosuppressive functions of IDO1/TDO-mediated tryptophan catabolism. Extrahepatic and hepatic cells express indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) to consume tryptophan and give rise to numerous bioactive metabolites such as kynurenine. Elevated expression of IDO1 or TDO, such as in cancer, increases the relative kynurenine levels while reducing tryptophan content. Kynurenine enters cells via System L transporters. (A) Increased kynurenine levels inhibit proliferation of T-cells and natural killer (NK) cells by interacting with aryl hydrocarbon receptor (AhR) to express programmed cell death protein 1 (PD-1). Previous studies have suggested the involvement of the general control non-deprepressible-2 (GCN2) kinase and mammalian target of rapamycin (mTOR) in proliferation inhibition but the exact mechanism through which this occurs still remains unresolved. (B) Kynurenine induces differentiation of naïve CD4⁺ T-cells to immunosuppressive T-regulatory cells by activation of AhR and induction of the FoxP3 transcription factor. Taken together, an immune suppressed tumour microenvironment is created that promotes survival of cancer cells.

Figure 2

Reversing IDO1/TDO-mediated immunosuppression by increasing the levels of System L transporter substrates to limit kynurenine entry into T-cells. (A) In tumour microenvironment rich in indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO), the tryptophan to kynurenine ratio is typically low leading to the suppression of T-cell activity and tumour killing. Blockade of TDO enzymatic activity by small molecule inhibitors (2) and/or supplementation with System L substrates such as leucine (1) is expected to increase their blood levels. Hence, the ratio of System L substrates to kynurenine in the tumour microenvironment (B) will also be increased. Elevated System L substrate levels competitively inhibit kynurenine entry into T cells so that T cell suppression is reduced.