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      Targeting the indoleamine 2,3-dioxygenase pathway in cancer

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          Abstract

          Tumor cells escape the immune surveillance system of the host through a process called immune tolerance. Immunotherapy targets molecules that serve as checks and balances in the regulation of immune response. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which through the process of tryptophan depletion exerts an immunosuppressive effect, facilitating immune escape of tumors. This review summarizes our current knowledge on IDO expression in malignancies, the IDO inhibitors that are currently available and those under clinical development.

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          Indoleamine 2,3 dioxygenase and metabolic control of immune responses.

          David Munn, Andrew L Mellor (2013)
          Sustained access to nutrients is a fundamental biological need, especially for proliferating cells, and controlling nutrient supply is an ancient strategy to regulate cellular responses to stimuli. By catabolizing the essential amino acid TRP, cells expressing the enzyme indoleamine 2,3 dioxygenase (IDO) can mediate potent local effects on innate and adaptive immune responses to inflammatory insults. Here, we discuss recent progress in elucidating how IDO activity promotes local metabolic changes that impact cellular and systemic responses to inflammatory and immunological signals. These recent developments identify potential new targets for therapy in a range of clinical settings, including cancer, chronic infections, autoimmune and allergic syndromes, and transplantation. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase.

            David Munn, Madhav D. Sharma, Babak Baban … (2005)
            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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              BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma.

              Dennie Frederick, Adriano Piris, Alexandria Cogdill … (2013)
              To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma. Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10 to 14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib) and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T-cell markers, and immunomodulatory cytokines. Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T-cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 was increased on treatment. A decrease in melanoma antigen expression and CD8 T-cell infiltrate was noted at time of progression on BRAF inhibitor alone and was reversed with combined BRAF and MEK inhibition. Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T-cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma. ©2013 AACR.
              Article 0 comments Cited 332 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yong Wha Moon: doctormoon7@gmail.com
                Joud Hajjar: joud.hajjar@bcm.edu
                Patrick Hwu: phwu@mdanderson.org
                Aung Naing: (713) 792-2950 , anaing@mdanderson.org
                Journal
                Journal ID (nlm-ta): J Immunother Cancer
                Journal ID (iso-abbrev): J Immunother Cancer
                Title: Journal for Immunotherapy of Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 2051-1426
                Publication date (Electronic): 15 December 2015
                Publication date PMC-release: 15 December 2015
                Publication date Collection: 2015
                Volume: 3
                Electronic Location Identifier: 51
                Affiliations
                [ ]Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do 463-712 South Korea
                [ ]Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 455, Houston, TX 77030 USA
                [ ]Section of Immunology, Allergy & Rheumatology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX 77030 USA
                [ ]Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
                Article
                Publisher ID: 94
                DOI: 10.1186/s40425-015-0094-9
                PMC ID: 4678703
                PubMed ID: 26674411
                SO-VID: 974839e0-c2b5-46ea-91aa-f9015c1e29fd
                Copyright © © Moon et al. 2015
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 9 July 2015
                Date accepted : 13 October 2015
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2015

                Keywords: indoleamine 2,3-dioxygenase,ido inhibitors,immune surveillance,immunomodulatory,malignancy
                Data availability:
                Keywords: indoleamine 2,3-dioxygenase, ido inhibitors, immune surveillance, immunomodulatory, malignancy

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