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Clin Cancer Res. 2015 Dec 15;21(24):5427-33. doi: 10.1158/1078-0432.CCR-15-0420. Epub 2015 Oct 30.

Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy.

Author information

1
Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
2
Department of Pathology, The University of Chicago, Chicago, Illinois.
3
Department of Pathology, The University of Chicago, Chicago, Illinois. Committee on Cancer Biology, The University of Chicago, Chicago, Illinois.
4
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.
5
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.

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.

PMID:
26519060
PMCID:
PMC4681601
DOI:
10.1158/1078-0432.CCR-15-0420
[Indexed for MEDLINE]
Free PMC Article

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