title: Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy.
abstract: Indoleamine 2, 3-dioxygenase 1 (IDO1), IDO2, and tryptophan 2, 3-dioxygenase (TDO) comprise a family of enzymes that catalyze the first- and rate-limiting step associated with the catabolic conversion of tryptophan (Trp) into kynurenine (Kyn). Through subsequent enzymatic and spontaneous reactions, Kyn is further converted into the energetic substrates, NAD(+) and ATP, to fuel cellular metabolic functions. Coincidently, the depletion of Trp and accumulation of Kyn has been demonstrated to induce effector T-cell apoptosis/dysfunction and immunosuppressive regulatory T-cell induction, respectively. Similar to other immune checkpoints, IDO1 and TDO are suggested to be important targets for immunotherapeutic intervention. This is represented by the recent growth of efforts to inhibit the Trp-to-Kyn pathway as a means to control immunosuppression. Inhibitors currently in clinical trials, INCB024360, GDC-0919, indoximod, and an IDO1 peptide-based vaccine, are being evaluated for their efficacy against a wide range of cancers including melanoma, glioblastoma, non-small cell lung, pancreatic, and/or breast cancer, as well as metastatic disease. Despite the rapid development of potent clinical grade inhibitors, strategic questions remain. Here, we review the state of the literature with respect to current therapeutic inhibitors of tryptophan catabolism, evaluation of those efforts preclinically and clinically, compensatory changes that occur with therapeutic targeting, as well as newly recognized signaling features that raise critical questions to the field. Given the rapidly evolving interest in determining how IDO1/TDO, and to an unknown extent, IDO2, can be targeted for increasing cancer immunotherapeutic efficacy, we present a brief but comprehensive analysis that addresses critical questions, while highlighting the mechanics that remain to be explored.
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhai
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Stefani
authors.initials: S
authors.lastname: Spranger
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois. Committee on Cancer Biology, The University of Chicago, Chicago, Illinois.
authors.forename: David C
authors.initials: DC
authors.lastname: Binder
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Galina
authors.initials: G
authors.lastname: Gritsina
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Lauing
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Northwestern University, Chicago, Illinois. Division of Hematology and Oncology, Northwestern University, Chicago, Illinois. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Northwestern Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois. derekwainwright@northwestern.edu.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Wainwright
mesh_terms: D000818:Animals; D002384:Catalysis / Q000187:drug effects; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007167:Immunotherapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D015398:Signal Transduction / Q000187:drug effects; D057170:Translational Research, Biomedical; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D014366:Tryptophan Oxygenase