Review Tryptophan Catabolism in Cancer: Beyond IDO and Tryptophan Depletion Michael Platten 1,2 , Wolfgang Wick 1,3 , and Benoît J. Van den Eynde 4 Abstract Tryptophan catabolism in cancer is increasingly being recognized as an important microenvironmental factor that suppresses antitumor immune responses. It has been proposed that the essential amino acid tryptophan is catabolized in the tumor tissue by the rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO) expressed in tumor cells or antigen-presenting cells. This metabolic pathway creates an immunosuppressive milieu in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites. Competitive inhibitors of IDO are currently being tested in clinical trials in patients with solid cancer, with the aim of enhancing the efficacy of conventional chemotherapy. There are, however, certain tumor types that are capable of catabolizing tryptophan but are largely IDO-negative. Recent evidence from studies in malignant gliomas and other types of cancers points to alternative enzymatic pathways of tryptophan catabolism involving tryptophan-2,3-dioxygenase (TDO). TDO, which is considered responsible for regulating systemic tryptophan levels in the liver, is constitutively expressed in some cancers and is equally capable of suppressing antitumor immune responses. Depletion of tryptophan induces signaling events in T cells, leading to anergy and apoptosis; however, active immunomodulation by accumulating tryptophan catabolites, most notably kynurenine, appears to play an equally important role. These immuno- modulatory effects of kynurenine are mediated by the aryl hydrocarbon receptor. This intracellular transcription factor has classically been viewed as a receptor for environmental toxins, such as dioxin, and its important role in influencing immune responses, especially in epithelial barriers, is only beginning to emerge. This review summarizes the exciting developments in our understanding of tryptophan catabolism as a key factor in the immunobiology of cancer. Cancer Res; 72(21); 5435–40. Ó2012 AACR. Introduction Two decades after the importance of tryptophan catabolism for maintaining the immune privilege of the placenta was discovered (1), increasing evidence is extending its biological relevance beyond immune tolerance to non-self. According to the generally accepted concept, tryptophan, an essential amino acid, is catabolized in the local microenvironment of tumors, immune-privileged sites, or sites of inflammation (2). In these tissues, cancer cells, immune cells, or specialized epithelial cells (e.g., syncytiotrophoblasts in the placenta) create an environment that suppresses antigen-specific T-cell responses both by depletion of tryptophan and by accumulation of immunosuppressive tryptophan catabolites. Because trypto- phan catabolism is induced by inflammatory mediators, nota- bly IFN-g , it is thought to represent an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology. In the context of cancer, this feedback loop may not be beneficial, as tryptophan catabolism has been implicated in inflammation-driven cancers such as colon cancer (3). There is strong evidence that suppression of anti- tumor immune responses in precancerous lesions and estab- lished cancers by tryptophan catabolism promotes tumor growth, which would make such catabolism an attractive target for therapeutic intervention (4). Hence, a considerable effort is being made to identify selective and efficient inhibitors of tryptophan catabolism, and methylated tryptophan, which enhances the efficacy of conventional chemotherapy in pre- clinical models, is currently being tested in clinical trials. In addition, the extent of tryptophan catabolism measured in serum and other biological fluids may serve as a biomarker for monitoring disease activity and response to therapy in cancer patients. Despite considerable advances in our understanding of this metabolic pathway, a number of questions remain unresolved, revolving mainly around (i) the redundancy of indoleamine- 2,3-dioxygenase (IDO) as the key and rate-limiting enzyme of tryptophan catabolism, and (ii) the molecular targets and 5435 Authors' Affiliations: 1 Department of Neurooncology, University Hospital Heidelberg, and 2 Experimental Neuroimmunology Unit, and 3 Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 4 Ludwig Institute for Cancer Research, Brussels Branch, and WELBIO, de Duve Institute, Universit e Catholique de Louvain, Brussels, Belgium Corresponding Author: Michael Platten, Department of Neurooncology, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany. Phone: 49-6221-56-6804; Fax: 49-6221-56-7554; E-mail: michael.platten@med.uni-heidelberg.de doi: 10.1158/0008-5472.CAN-12-0569 Ó2012 American Association for Cancer Research. 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