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      Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies

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          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.

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          Most cited references71

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          GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase.

          Indoleamine 2,3 dioxygenase (IDO) catabolizes the amino acid tryptophan. IDO-expressing immunoregulatory dendritic cells (DCs) have been implicated in settings including tumors, autoimmunity, and transplant tolerance. However, the downstream molecular mechanisms by which IDO functions to regulate T cell responses remain unknown. We now show that IDO-expressing plasmacytoid DCs activate the GCN2 kinase pathway in responding T cells. GCN2 is a stress-response kinase that is activated by elevations in uncharged tRNA. T cells with a targeted disruption of GCN2 were not susceptible to IDO-mediated suppression of proliferation in vitro. In vivo, proliferation of GCN2-knockout T cells was not inhibited by IDO-expressing DCs from tumor-draining lymph nodes. IDO induced profound anergy in responding wild-type T cells, but GCN2-knockout cells were refractory to IDO-induced anergy. We hypothesize that GCN2 acts as a molecular sensor in T cells, allowing them to detect and respond to conditions created by IDO.
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            Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism.

            Although an immunoregulatory role of aryl hydrocarbon receptor (Ahr) has been demonstrated in T cells and macrophages, little is known about its function in dendritic cells (DC). Here, we show that lipopolysaccharide (LPS) and CpG stimulate Ahr expression in bone marrow-derived dendritic cells (BMDC). Furthermore, we found that Ahr is required to induce indoleamine 2,3-dioxygenase (IDO) expression, an immunosuppressive enzyme that catabolizes tryptophan into kynurenine (Kyn) and other metabolites in DC. In the presence of LPS or CpG, Ahr-deficient (Ahr(-/-)) mature BMDC induced immune responses characterized by reduced Kyn and IL-10 production compared with results observed with tolerogenic mature WT BMDC. In a coculture system with LPS- or CpG-stimulated BMDC and naive T cells, Ahr(-/-) BMDC inhibited naive T-cell differentiation into regulatory T (Treg) cells, which likely facilitated Th17 cell development and promoted naive T-cell proliferation. Addition of synthetic L-Kyn to the coculture system skewed the differentiation of naive T cells to Treg cells rather than Th17 cells. Taken together, our results demonstrate a previously unknown negatively regulatory role for Ahr in DC-mediated immunogenesis in the presence of LPS or CpG, which, in turn, alters the Kyn-dependent generation of Treg cells and Th17 cells from naive T cells.
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              Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling.

              Inflammatory signaling plays a key role in tumor progression, and the pleiotropic cytokine interleukin-6 (IL-6) is an important mediator of protumorigenic properties. Activation of the aryl hydrocarbon receptor (AHR) with exogenous ligands coupled with inflammatory signals can lead to synergistic induction of IL6 expression in tumor cells. Whether there are endogenous AHR ligands that can mediate IL6 production remains to be established. The indoleamine-2,3-dioxygenase pathway is a tryptophan oxidation pathway that is involved in controlling immune tolerance, which also aids in tumor escape. We screened the metabolites of this pathway for their ability to activate the AHR; results revealed that kynurenic acid (KA) is an efficient agonist for the human AHR. Structure-activity studies further indicate that the carboxylic acid group is required for significant agonist activity. KA is capable of inducing CYP1A1 messenger RNA levels in HepG2 cells and inducing CYP1A-mediated metabolism in primary human hepatocytes. In a human dioxin response element-driven stable reporter cell line, the EC(25) was observed to be 104nM, while in a mouse stable reporter cell line, the EC(25) was 10muM. AHR ligand competition binding assays revealed that KA is a ligand for the AHR. Treatment of MCF-7 cells with interleukin-1beta and a physiologically relevant concentration of KA (e.g., 100nM) leads to induction of IL6 expression that is largely dependent on AHR expression. Our findings have established that KA is a potent AHR endogenous ligand that can induce IL6 production and xenobiotic metabolism in cells at physiologically relevant concentrations.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                16 June 2020
                2020
                : 11
                : 1185
                Affiliations
                [1] 1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [2] 2Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [3] 3Robert H. Lurie Comprehensive Cancer Center of Northwestern University , Chicago, IL, United States
                [4] 4Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [5] 5Department of Urology, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [6] 6Department of Dermatology, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [7] 7Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [8] 8Division of Neuro-Oncology, Department of Neurology, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [9] 9Department of Pharmacology, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [10] 10Transgenic and Targeted Mutagenesis Laboratory, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [11] 11Center for Molecular Innovation and Drug Discovery, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States
                [12] 12Department of Animal Sciences, University of Illinois at Urbana-Champaign , Urbana, IL, United States
                Author notes

                Edited by: Alexander Muller, Lankenau Institute for Medical Research, United States

                Reviewed by: Graham Robert Leggatt, The University of Queensland, Australia; Kawaljit Kaur, University of California, Los Angeles, United States

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.01185
                7308527
                32612606
                d9b2dede-9ba4-4f04-9471-fcd26f303be3
                Copyright © 2020 Zhai, Bell, Ladomersky, Lauing, Bollu, Sosman, Zhang, Wu, Miller, Meeks, Lukas, Wyatt, Doglio, Schiltz, McCusker and Wainwright.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 February 2020
                : 13 May 2020
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 119, Pages: 15, Words: 12041
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke 10.13039/100000065
                Award ID: R01NS097851
                Funded by: National Cancer Institute 10.13039/100000054
                Award ID: P50CA221747
                Categories
                Immunology
                Review

                Immunology
                aging,immunotherapy,glioblastoma,tryptophan,immunosuppression,treg,ido1,kynurenine
                Immunology
                aging, immunotherapy, glioblastoma, tryptophan, immunosuppression, treg, ido1, kynurenine

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