Targeting tryptophan availability to tumors: the answer to immune escape?

Tumoral immune escape is an obstacle to successful cancer therapy. Tryptophan (Trp) metabolites along the kynurenine pathway induce immunosuppression involving apoptosis of effector immune cells, which tumors use to escape an immune response. Production of these metabolites is initiated by indoleamine 2,3‐dioxygenase (IDO1). IDO1 inhibitors, however, do not always overcome the immune escape and another enzyme expressed in tumors, Trp 2,3‐dioxygenase (TDO2), has been suggested as the reason. However, without Trp, tumors cannot achieve an immune escape through either enzyme. Trp is therefore key to immune escape. In this perspective paper, Trp availability to tumors will be considered and strategies limiting it proposed. One major determinant of Trp availability is the large increase in plasma free (non‐albumin‐bound) Trp in cancer patients, caused by the low albumin and the high non‐esterified fatty acid (NEFA) concentrations in plasma. Albumin infusions, antilipolytic therapy or both could be used, if indicated, as adjuncts to immunotherapy and other therapies. Inhibition of amino acid uptake by tumors is another strategy and α‐methyl‐DL‐tryptophan or other potential inhibitors could fulfill this role. Glucocorticoid receptor antagonists may have a role in preventing glucocorticoid induction of TDO in host liver and tumors expressing it and in undermining the permissive effect of glucocorticoids on IDO1 induction by cytokines. Nicotinamide may be a promising TDO2 inhibitor lacking disadvantages of current inhibitors. Establishing the Trp disposition status of cancer patients and in various tumor types may provide the information necessary to formulate tailored therapeutic approaches to cancer immunotherapy that can also undermine tumoral immune escape. Targeting availability of the amino acid tryptophan to tumors is the key to overcoming tumoral immune escape. Proposed strategies include lowering plasma free tryptophan levels by albumin infusions and antilipolytic drugs, inhibition of tumoral uptake of tryptophan by inhibitors of amino acid transporter function, and modulation of activities of the tryptophan‐degrading enzymes indoleamine 2,3‐dioxygenase and tryptophan 2,3‐dioxygenase by specific inhibitors, glucocorticoid receptor antagonists and nicotinamide. Establishing the Trp disposition status of cancer patients and in various tumor types may provide the information necessary to formulate tailored therapeutic approaches to cancer immunotherapy that c