For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
37
views
29
references
 Top references
cited by
138
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      859
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: not found

      Reversal of IDO-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Elevated tryptophan (Trp) catabolism in the tumor microenvironment (TME) can mediate immune suppression by upregulation of IFNg-inducible indoleamine 2,3-dioxygenase (IDO1) and/or ectopic expression of the predominantly liver-restricted enzyme tryptophan 2,3-dioxygenase (TDO) 1– 5 . Whether these effects are due to Trp depletion in the TME or are mediated by the accumulation of the IDO1/TDO product Kynurenine (Kyn) remains controversial 5– 13 . Here we show that administration of a pharmacologically optimized enzyme (PEGylated Kynureninase) that degrades Kyn into immunologically inert, non-toxic and readily-cleared metabolites inhibits tumor growth. Enzyme treatment is associated with a marked increase in the tumor infiltration and proliferation of polyfunctional CD8 + lymphocytes. We show that PEG-Kynureninase administration has substantial therapeutic effects when combined with approved checkpoint inhibitors or with a cancer vaccine for the treatment of large B16-F10 melanoma, 4T1 breast carcinoma or CT26 colon carcinoma tumors. PEG-Kynureninase mediates prolonged depletion of Kyn in the TME and reverses the modulatory effects of IDO1/TDO upregulation in the tumor microenvironment.

          Related collections

          Most cited references29

          • Record: found
          • Abstract: found
          • Article: not found

          Over-production of proteins in Escherichia coli: mutant hosts that allow synthesis of some membrane proteins and globular proteins at high levels.

          B Miroux, J. Walker (1996)
          We have investigated the over-production of seven membrane proteins in an Escherichia coli-bacteriophage T7 RNA polymerase expression system. In all seven cases, when expression of the target membrane protein was induced, most of the BL21(DE3) host cells died. Similar effects were also observed with expression vectors for ten globular proteins. Therefore, protein over-production in this expression system is either limited or prevented by bacterial cell death. From the few survivors of BL21(DE3) expressing the oxoglutarate-malate carrier protein from mitochondrial membranes, a mutant host C41(DE3) was selected that grew to high saturation cell density, and produced the protein as inclusion bodies at an elevated level without toxic effect. Some proteins that were expressed poorly in BL21(DE3), and others where the toxicity of the expression plasmids prevented transformation into this host, were also over-produced successfully in C41(DE3). The examples include globular proteins as well as membrane proteins, and therefore, strain C41(DE3) is generally superior to BL21(DE3) as a host for protein over-expression. However, the toxicity of over-expression of some of the membrane proteins persisted partially in strain C41(DE3). Therefore, a double mutant host C43(DE3) was selected from C41(DE3) cells containing the expression plasmid for subunit b of bacterial F-ATPase. In strain C43(DE3), both subunits b and c of the F-ATPase, an alanine-H(+) symporter, and the ADP/ATP and the phosphate carriers from mitochondria were all over-produced. The transcription of the gene for the OGCP and subunit b was lower in C41(DE3) and C43(DE3), respectively, than in BL21(DE3). In C43(DE3), the onset of transcription of the gene for subunit b was delayed after induction, and the over-produced protein was incorporated into the membrane. The procedure used for selection of C41(DE3) and C43(DE3) could be employed to tailor expression hosts in order to overcome other toxic effects associated with over-expression.
          Article 0 comments Cited 396 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion.

            Michael Platten, Wolfgang Wick, Benoît van den Eynde (2012)
            Tryptophan catabolism in cancer is increasingly being recognized as an important microenvironmental factor that suppresses antitumor immune responses. It has been proposed that the essential amino acid tryptophan is catabolized in the tumor tissue by the rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO) expressed in tumor cells or antigen-presenting cells. This metabolic pathway creates an immunosuppressive milieu in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites. Competitive inhibitors of IDO are currently being tested in clinical trials in patients with solid cancer, with the aim of enhancing the efficacy of conventional chemotherapy. There are, however, certain tumor types that are capable of catabolizing tryptophan but are largely IDO-negative. Recent evidence from studies in malignant gliomas and other types of cancers points to alternative enzymatic pathways of tryptophan catabolism involving tryptophan-2,3-dioxygenase (TDO). TDO, which is considered responsible for regulating systemic tryptophan levels in the liver, is constitutively expressed in some cancers and is equally capable of suppressing antitumor immune responses. Depletion of tryptophan induces signaling events in T cells, leading to anergy and apoptosis; however, active immunomodulation by accumulating tryptophan catabolites, most notably kynurenine, appears to play an equally important role. These immunomodulatory effects of kynurenine are mediated by the aryl hydrocarbon receptor. This intracellular transcription factor has classically been viewed as a receptor for environmental toxins, such as dioxin, and its important role in influencing immune responses, especially in epithelial barriers, is only beginning to emerge. This review summarizes the exciting developments in our understanding of tryptophan catabolism as a key factor in the immunobiology of cancer. ©2012 AACR.
            Article 0 comments Cited 273 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells

              Peter Terness, Thomas Bauer, Lars Röse … (2002)
              Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed in certain cells and tissues, particularly in antigen-presenting cells of lymphoid organs and in the placenta. It was shown that IDO prevents rejection of the fetus during pregnancy, probably by inhibiting alloreactive T cells, and it was suggested that IDO-expression in antigen-presenting cells may control autoreactive immune responses. Degradation of tryptophan, an essential amino acid required for cell proliferation, was reported to be the mechanism of IDO-induced T cell suppression. Because we wanted to study the action of IDO-expressing dendritic cells (DCs) on allogeneic T cells, the human IDO gene was inserted into an adenoviral vector and expressed in DCs. Transgenic DCs decreased the concentration of tryptophan, increased the concentration of kynurenine, the main tryptophan metabolite, and suppressed allogeneic T cell proliferation in vitro. Kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, but no other IDO-induced tryptophan metabolites, suppressed the T cell response, the suppressive effects being additive. T cells, once stopped in their proliferation, could not be restimulated. Inhibition of proliferation was likely due to T cell death because suppressive tryptophan catabolites exerted a cytotoxic action on CD3+ cells. This action preferentially affected activated T cells and increased gradually with exposure time. In addition to T cells, B and natural killer (NK) cells were also killed, whereas DCs were not affected. Our findings shed light on suppressive mechanisms mediated by DCs and provide an explanation for important biological processes in which IDO activity apparently is increased, such as protection of the fetus from rejection during pregnancy and possibly T cell death in HIV-infected patients.
              Article 0 comments Cited 235 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9604648
                Journal ID (pubmed-jr-id): 20305
                Journal ID (nlm-ta): Nat Biotechnol
                Journal ID (iso-abbrev): Nat. Biotechnol.
                Title: Nature biotechnology
                ISSN (Print): 1087-0156
                ISSN (Electronic): 1546-1696
                Publication date Nihms-submitted: 4 June 2018
                Publication date (Electronic): 16 July 2018
                Publication date (Print): September 2018
                Publication date PMC-release: 16 January 2019
                Volume: 36
                Issue: 8
                Pages: 758-764
                Affiliations
                [1 ]Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA
                [2 ]Department of Oncology, University of Texas Dell Medical School, LiveSTRONG Cancer Institutes, Austin, Texas, USA
                [3 ]Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA
                [4 ]Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, New Jersey, USA
                [5 ]MedImmune LLC, 1 MedImmune Way, Gaithersburg, Maryland, 20878
                [6 ]Kyn Therapeutics, 400 Technology Sq., Cambridge, Massachusetts, 02139
                [7 ]Department of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Kyoto, Japan
                [8 ]Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA
                [9 ]Heat Biologics Inc. Durham North Carolina, USA
                Author notes
                [* ]Correspondence should be addressed to E.S. ( stonesci@ 123456utexas.edu ) or to G.G. ( gg@ 123456che.utexas.edu )
                [10]

                These authors contributed equally to this work.

                Article
                Manuscript ID: NIHMS972462
                DOI: 10.1038/nbt.4180
                PMC ID: 6078800
                PubMed ID: 30010674
                SO-VID: 8f9f7a8c-1588-475c-b602-8e9074000924
                License:

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Subject: Article

                ScienceOpen disciplines: Biotechnology
                Data availability:
                ScienceOpen disciplines: Biotechnology

                Comments

                Comment on this article

                scite_

                Similar content859

                See all similar

                Cited by134

                See all cited by

                Most referenced authors668

                See all reference authors