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Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies.
Front Immunol. 2020; 11:1185.FI

Abstract

Indoleamine 2, 3-dioxygenase 1 (IDO; IDO1; INDO) is a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan, into downstream kynurenines. Canonically, the metabolic depletion of tryptophan and/or the accumulation of kynurenine is the mechanism that defines how immunosuppressive IDO inhibits immune cell effector functions and/or facilitates T cell death. Non-canonically, IDO also suppresses immunity through non-enzymic effects. Since IDO targeting compounds predominantly aim to inhibit metabolic activity as evidenced across the numerous clinical trials currently evaluating safety/efficacy in patients with cancer, in addition to the recent disappointment of IDO enzyme inhibitor therapy during the phase III ECHO-301 trial, the issue of IDO non-enzyme effects have come to the forefront of mechanistic and therapeutic consideration(s). Here, we review enzyme-dependent and -independent IDO-mediated immunosuppression as it primarily relates to glioblastoma (GBM); the most common and aggressive primary brain tumor in adults. Our group's recent discovery that IDO levels increase in the brain parenchyma during advanced age and regardless of whether GBM is present, highlights an immunosuppressive synergy between aging-increased IDO activity in cells of the central nervous system that reside outside of the brain tumor but collaborate with GBM cell IDO activity inside of the tumor. Because of their potential value for the in vivo study of IDO, we also review current transgenic animal modeling systems while highlighting three new constructs recently created by our group. This work converges on the central premise that maximal immunotherapeutic efficacy in subjects with advanced cancer requires both IDO enzyme- and non-enzyme-neutralization, which is not adequately addressed by available IDO-targeting pharmacologic approaches at this time.

Authors+Show Affiliations

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States.Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States. Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States. Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States. Division of Neuro-Oncology, Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Transgenic and Targeted Mutagenesis Laboratory, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Transgenic and Targeted Mutagenesis Laboratory, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States. Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Center for Molecular Innovation and Drug Discovery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States.Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States. Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

32612606

Citation

Zhai, Lijie, et al. "Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies." Frontiers in Immunology, vol. 11, 2020, p. 1185.
Zhai L, Bell A, Ladomersky E, et al. Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies. Front Immunol. 2020;11:1185.
Zhai, L., Bell, A., Ladomersky, E., Lauing, K. L., Bollu, L., Sosman, J. A., Zhang, B., Wu, J. D., Miller, S. D., Meeks, J. J., Lukas, R. V., Wyatt, E., Doglio, L., Schiltz, G. E., McCusker, R. H., & Wainwright, D. A. (2020). Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies. Frontiers in Immunology, 11, 1185. https://doi.org/10.3389/fimmu.2020.01185
Zhai L, et al. Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies. Front Immunol. 2020;11:1185. PubMed PMID: 32612606.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies. AU - Zhai,Lijie, AU - Bell,April, AU - Ladomersky,Erik, AU - Lauing,Kristen L, AU - Bollu,Lakshmi, AU - Sosman,Jeffrey A, AU - Zhang,Bin, AU - Wu,Jennifer D, AU - Miller,Stephen D, AU - Meeks,Joshua J, AU - Lukas,Rimas V, AU - Wyatt,Eugene, AU - Doglio,Lynn, AU - Schiltz,Gary E, AU - McCusker,Robert H, AU - Wainwright,Derek A, Y1 - 2020/06/16/ PY - 2020/02/01/received PY - 2020/05/13/accepted PY - 2020/7/3/entrez PY - 2020/7/3/pubmed PY - 2020/7/3/medline KW - IDO1 KW - Treg KW - aging KW - glioblastoma KW - immunosuppression KW - immunotherapy KW - kynurenine KW - tryptophan SP - 1185 EP - 1185 JF - Frontiers in immunology JO - Front Immunol VL - 11 N2 - Indoleamine 2, 3-dioxygenase 1 (IDO; IDO1; INDO) is a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan, into downstream kynurenines. Canonically, the metabolic depletion of tryptophan and/or the accumulation of kynurenine is the mechanism that defines how immunosuppressive IDO inhibits immune cell effector functions and/or facilitates T cell death. Non-canonically, IDO also suppresses immunity through non-enzymic effects. Since IDO targeting compounds predominantly aim to inhibit metabolic activity as evidenced across the numerous clinical trials currently evaluating safety/efficacy in patients with cancer, in addition to the recent disappointment of IDO enzyme inhibitor therapy during the phase III ECHO-301 trial, the issue of IDO non-enzyme effects have come to the forefront of mechanistic and therapeutic consideration(s). Here, we review enzyme-dependent and -independent IDO-mediated immunosuppression as it primarily relates to glioblastoma (GBM); the most common and aggressive primary brain tumor in adults. Our group's recent discovery that IDO levels increase in the brain parenchyma during advanced age and regardless of whether GBM is present, highlights an immunosuppressive synergy between aging-increased IDO activity in cells of the central nervous system that reside outside of the brain tumor but collaborate with GBM cell IDO activity inside of the tumor. Because of their potential value for the in vivo study of IDO, we also review current transgenic animal modeling systems while highlighting three new constructs recently created by our group. This work converges on the central premise that maximal immunotherapeutic efficacy in subjects with advanced cancer requires both IDO enzyme- and non-enzyme-neutralization, which is not adequately addressed by available IDO-targeting pharmacologic approaches at this time. SN - 1664-3224 UR - https://www.unboundmedicine.com/medline/citation/32612606/Immunosuppressive_IDO_in_Cancer:_Mechanisms_of_Action,_Animal_Models,_and_Targeting_Strategies L2 - https://doi.org/10.3389/fimmu.2020.01185 DB - PRIME DP - Unbound Medicine ER -
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