Cancer Immunology at the Crossroads: Experimental Immunotherapies Tumoral Immune Resistance Mediated by Enzymes That Degrade Tryptophan

Cancer patients mount T-lymphocyte responses against antigens expressed selectively by their malignancy, but these responses often fail to control their disease, because tumors select mechanisms that allow them to resist immune destruction. Among the numerous resistance mechanisms that have been proposed, metabolic inhibition of T cells by tryptophan catabolism deserves particular attention, because of the frequent expression of tryptophan-degrading enzymes in human tumors, and because in vitro and in vivo studies have shown that their enzymatic activity can be readily blocked by pharmacologic inhibitors, thereby restoring T-cell–mediated tumor cell killing and paving the way to targeted therapeutic intervention. In view of recent observations, and taking into account the differences between human and mouse data that differ in several aspects, in this Cancer Immunology at the Crossroads article, we discuss the role of the three enzymes that have been proposed to control tryptophan catabolism in tumoral immune resistance: indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO), and indoleamine 2,3-dioxygenase 2 (IDO2). Cancer Immunol Res; 3(9); 978–85. 2015 AACR.