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.