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

Abstract

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.

Tryptophan Metabolism: A Versatile Area Providing Multiple Targets for Pharmacological Intervention

“…This will be discussed further under 3 (the hydroxylation or serotonin pathway). Targeting Trp availability to tumors has recently been proposed [13] to overcome tumoral immune escape. Here, decreasing plasma free [Trp] using antilipolytic agents, albumin infusions or both has been suggested.…”

“…Targeting Trp availability to tumors has been suggested as a strategy to overcome tumoral immune escape [13]. Tumors need Trp and other nutrients to stimulate their growth and proliferation.…”

“…Consequently, strategies aimed at maintaining effector T cell function by ensuring that tumoral [Trp] remains above 10 μ M should be pursued in conjunction with strategies preventing production of immunosuppressive kynurenines, namely those involving inhibition of IDO/TDO upregulation and limiting Trp availability to tumors. In human colon and stomach cancer tissues, tumoral [Trp] can reach 70 and 40 μ M respectively and a much higher value (270 μ M) has been reported in a mouse model of CT26 colon carcinoma (for references, see [13]). In the above proposed targeting strategy [13], inhibition of amino acid transporter function by α -MT is the first line of action.…”

“…In human colon and stomach cancer tissues, tumoral [Trp] can reach 70 and 40 μ M respectively and a much higher value (270 μ M) has been reported in a mouse model of CT26 colon carcinoma (for references, see [13]). In the above proposed targeting strategy [13], inhibition of amino acid transporter function by α -MT is the first line of action. Decreasing plasma free Trp availability to tumors, which is enhanced in cancer through decreased albumin and increased NEFA, could be achieved by albumin infusions and use of antilipolytic agents, e.g.…”

Circular RNA circZNF566 promotes hepatocellular carcinoma progression by sponging miR-4738-3p and regulating TDO2 expression

“…TDO2 is a homotetrameric cytosolic enzyme 14,34,35 that is expressed mainly in only the liver; it is the rate-limiting enzyme in the first step of Try metabolism in mammals and converts Try to produce Kyn 36,37 . The use by tumors of proinflammatory Kyn metabolites such as 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid to undermine the immune system and achieve immune escape [38][39][40] . TDO2 was first found to be (see figure on previous page) Fig.…”