IL4i1 and IDO1: Oxidases that control a tryptophan metabolic nexus in cancer
2023; Elsevier BV; Volume: 299; Issue: 6 Linguagem: Inglês
10.1016/j.jbc.2023.104827
ISSN1083-351X
AutoresLeonie Zeitler, Peter J. Murray,
Tópico(s)Immune cells in cancer
ResumoRegulated tryptophan metabolism by immune cells has been associated with the promotion of tolerance and poor outcomes in cancer. The main focus of research has centered on local tryptophan depletion by IDO1, an intracellular heme-dependent oxidase that converts tryptophan to formyl-kynurenine. This is the first step of a complex pathway supplying metabolites for de novo NAD+ biosynthesis, 1-carbon metabolism, and a myriad of kynurenine derivatives of which several act as agonists of the arylhydrocarbon receptor (AhR). Thus, cells that express IDO1 deplete tryptophan while generating downstream metabolites. We now know that another enzyme, the secreted L-amino acid oxidase IL4i1 also generates bioactive metabolites from tryptophan. In tumor microenvironments, IL4i1 and IDO1 have overlapping expression patterns, especially in myeloid cells, suggesting the two enzymes control a network of tryptophan-specific metabolic events. New findings about IL4i1 and IDO1 have shown that both enzymes generate a suite of metabolites that suppress oxidative cell death ferroptosis. Thus, within inflammatory environments, IL4i1 and IDO1 simultaneously control essential amino acid depletion, AhR activation, suppression of ferroptosis, and biosynthesis of key metabolic intermediates. Here, we summarize the recent advances in this field, focusing on IDO1 and IL4i1 in cancer. We speculate that while inhibition of IDO1 remains a viable adjuvant therapy for solid tumors, the overlapping effects of IL4i1 must be accounted for, as potentially both enzymes may need to be inhibited at the same time to produce positive effects in cancer therapy. Regulated tryptophan metabolism by immune cells has been associated with the promotion of tolerance and poor outcomes in cancer. The main focus of research has centered on local tryptophan depletion by IDO1, an intracellular heme-dependent oxidase that converts tryptophan to formyl-kynurenine. This is the first step of a complex pathway supplying metabolites for de novo NAD+ biosynthesis, 1-carbon metabolism, and a myriad of kynurenine derivatives of which several act as agonists of the arylhydrocarbon receptor (AhR). Thus, cells that express IDO1 deplete tryptophan while generating downstream metabolites. We now know that another enzyme, the secreted L-amino acid oxidase IL4i1 also generates bioactive metabolites from tryptophan. In tumor microenvironments, IL4i1 and IDO1 have overlapping expression patterns, especially in myeloid cells, suggesting the two enzymes control a network of tryptophan-specific metabolic events. New findings about IL4i1 and IDO1 have shown that both enzymes generate a suite of metabolites that suppress oxidative cell death ferroptosis. Thus, within inflammatory environments, IL4i1 and IDO1 simultaneously control essential amino acid depletion, AhR activation, suppression of ferroptosis, and biosynthesis of key metabolic intermediates. Here, we summarize the recent advances in this field, focusing on IDO1 and IL4i1 in cancer. We speculate that while inhibition of IDO1 remains a viable adjuvant therapy for solid tumors, the overlapping effects of IL4i1 must be accounted for, as potentially both enzymes may need to be inhibited at the same time to produce positive effects in cancer therapy. The 20 proteinogenic amino acids sustain cellular biochemistry by: (i) translation, (ii) as a source of carbon skeletons and nitrogen for energy generation and nucleotide biosynthesis, and (iii) as "shuttles" to move molecules to different cellular compartments and tasks such as the malate-aspartate shuttle or methionine as a major methyl donor for the 1-carbon-folate cycle. Several amino acids have dedicated additional functions as precursors of key signaling molecules (neurotransmitters), cofactors (heme, from glycine), or redox protective molecules such as glutathione (from glycine, cysteine, and glutamate). Because of these diverse functions, cells balance their amino acid sources by synthesis, transport, and scavenging from protein sinks and therefore constantly monitor deficiencies or excesses of all amino acids. An additional facet of amino acid metabolism concerns the cellular and biochemical outcomes where a regulated enzyme consumes an essential amino acid and generates distinct products. In this setting, two events occur simultaneously: the essential amino acid can become limiting, triggering cellular defenses including increased amino acid transport, the reduction of translation, and activation of autophagy (and related cell protective measures) while also the products can have modulatory effects. We define "regulated" amino acid metabolism here as (i) the specific, induced expression or activity of amino acid metabolizing enzymes via cytokines, pathogen products, or other pathways, or (ii) the acquisition of enzyme expression not normally present in the cell type of interest. In the case of the latter, many cancer cells express amino acid metabolizing enzymes in patterns that differ from their cell of origin, presumably as a way to obtain resources to sustain growth or to evade immune control. The main amino acid-metabolizing enzymes regulated by cytokines are arginases (ARG1 in the cytoplasm and ARG2 in mitochondria), the tryptophan oxidases IDO1 (indole, 2,3 dioxygenase), and TDO2 (tryptophan dioxygenase) and IL4i1 (Interleukin 4-induced 1, a secreted oxidase) (1Murray P.J. Amino acid auxotrophy as a system of immunological control nodes.Nat. Immunol. 2016; 17: 132-139Google Scholar). Three of these enzymes also have constitutive functions: ARG1 and TDO2 metabolize dietary arginine and tryptophan in hepatocytes, while most cells express some ARG2 to control nitrogen metabolism in mitochondria. However, within cells of the immune system, these enzymes can be highly expressed and thereby consume arginine or tryptophan within local inflammatory microenvironments while at the same time generating bioactive products that have diverse and unexpected cellular effects (1Murray P.J. Amino acid auxotrophy as a system of immunological control nodes.Nat. Immunol. 2016; 17: 132-139Google Scholar, 2Grohmann U. Bronte V. Control of immune response by amino acid metabolism.Immunol. Rev. 2010; 236: 243-264Google Scholar). Accordingly, arginine and tryptophan metabolism intersect with many elements of immune regulation and cancer biology. In some cancer cell types, TDO2 and IDO1 expression can also be uncoupled from the regulatory signals that control enzyme expression in immune cells: We discuss this aspect briefly as a counterpoint to the immune functions of arginine and tryptophan metabolism. We note that the intersection of microbial metabolism of amino acids and especially indoles by the microbiota, with host physiology is an emerging and important topic (3Hezaveh K. Shinde R.S. Klotgen A. Halaby M.J. Lamorte S. Ciudad M.T. et al.Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.Immunity. 2022; 55: 324-340.e8Google Scholar, 4Roager H.M. Licht T.R. Microbial tryptophan catabolites in health and disease.Nat. Commun. 2018; 9: 3294Google Scholar). However, this element of amino acid metabolism is too large in scope to be included herein. Here, we focus on tryptophan metabolism by IDO1 and IL4i1. Summaries of the biology and clinical significance of arginase metabolism and TDO2 have been published (1Murray P.J. Amino acid auxotrophy as a system of immunological control nodes.Nat. Immunol. 2016; 17: 132-139Google Scholar, 2Grohmann U. Bronte V. Control of immune response by amino acid metabolism.Immunol. Rev. 2010; 236: 243-264Google Scholar, 5Platten M. Nollen E.A.A. Rohrig U.F. Fallarino F. Opitz C.A. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond.Nat. Rev. Drug Discov. 2019; 18: 379-401Google Scholar, 6Peranzoni E. Marigo I. Dolcetti L. Ugel S. Sonda N. Taschin E. et al.Role of arginine metabolism in immunity and immunopathology.Immunobiology. 2007; 212: 795-812Google Scholar, 7Eming S.A. Murray P.J. Pearce E.J. Metabolic orchestration of the wound healing response.Cell Metab. 2021; 33: 1726-1743Google Scholar) and will not be covered. Nevertheless, in a general sense, all the regulated arginine- and tryptophan-metabolizing enzymes cause similar biochemical outputs: an amino acid is consumed and a product generated. In this regard, practical and conceptual issues underline all experimental research on regulated amino acid metabolism. First, in the practical realm, quantification of the effects of amino acid metabolism is intrinsically complex as the temporal effects of depletion versus product generation need to be experimentally accounted for often in complex cellular environments. We also do not yet have a full understanding of the effects of cell-specific amino acid limitation, which may vary from cell to cell. Indeed, different cancer cells have substantial differences in their adaptation to malignant growth (8Shorthouse D. Bradley J. Critchlow S.E. Bendtsen C. Hall B.A. Heterogeneity of the cancer cell line metabolic landscape.Mol. Syst. Biol. 2022; 18e11006Google Scholar), while normal cells from muscle to neuron to T cell will naturally have diverse amino acid requirements linked to their specific functions. Further, we only have a rudimentary understanding of how cells detect amino acids (9Wolfson R.L. Sabatini D.M. The dawn of the age of amino acid sensors for the mTORC1 pathway.Cell Metab. 2017; 26: 301-309Google Scholar) and adjust their metabolism to source the correct amounts needed. Second, in a conceptual sense, a curiosity of regulated amino acid metabolism in the immune system via arginases, IDO1/TDO2 and IL4i1, is their arginine- and tryptophan-centric nature compared to other essential amino acids such as threonine or branched-chain amino acids. This specificity suggests the degradation versus product generation pathways from arginine and tryptophan have evolved for immune-specific tasks relative to all other amino acids. As we will discuss here, the knowledge of newly discovered biology from these pathways is rapidly advancing. Nevertheless, it is important to note that the limitation of different essential amino acids can have highly specific effects. For example, the limitation of valine specifically collapses complex one of the electron transport chain (10Thandapani P. Kloetgen A. Witkowski M.T. Glytsou C. Lee A.K. Wang E. et al.Valine tRNA levels and availability regulate complex I assembly in leukaemia.Nature. 2022; 601: 428-433Google Scholar), and dietary valine limitation eliminates stem cells from the bone marrow (11Taya Y. Ota Y. Wilkinson A.C. Kanazawa A. Watarai H. Kasai M. et al.Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation.Science. 2016; 354: 1152-1155Google Scholar). However, in both cases, valine amounts are controlled by experimental manipulation of the food or media rather than via a specific enzyme that controls valine degradation. By contrast, the biology we discuss here depends on the natural activity of endogenous enzymes that regulate amino acid limitation. IDO1 and IL4i1 are tryptophan-metabolizing enzymes upregulated in immune cells locally depleting tryptophan (and in the case of IL4i1, other aromatic amino acids) and generating immunomodulatory metabolites in their microenvironment (Fig. 1A). While IDO1 is an intracellular enzyme, IL4i1 is secreted (12Boulland M.L. Marquet J. Molinier-Frenkel V. Moller P. Guiter C. Lasoudris F. et al.Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation.Blood. 2007; 110: 220-227Google Scholar), suggesting that tryptophan metabolism by each enzyme occurs in a spatially separated manner. Thus, IDO1 and IL4i1 may operate simultaneously to catabolize tryptophan in the intra- and extracellular milieu. IDO1 catalyzes the oxidation of the tryptophan indole ring generating N-formyl-kynurenine which is the the first and rate-limiting reaction of the kynurenine (Kyn) pathway. This main tryptophan metabolic pathway generates key downstream Kyn metabolites and supplies substrates for the NAD+ de novo synthesis (13Covarrubias A.J. Perrone R. Grozio A. Verdin E. NAD(+) metabolism and its roles in cellular processes during ageing.Nat. Rev. Mol. Cell Biol. 2021; 22: 119-141Google Scholar, 14Cervenka I. Agudelo L.Z. Ruas J.L. Kynurenines: tryptophan's metabolites in exercise, inflammation, and mental health.Science. 2017; 357eaaf9794Google Scholar, 15Badawy A.A. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects.Int. J. Tryptophan Res. 2017; 101178646917691938Google Scholar) (Fig. 1B). N-formyl-Kyn is subsequently deformylated by the constitutively expressed arylformamidase (AFMID) to generate Kyn while the formyl group is a methyl donor for 1-carbon metabolism (16Newman A.C. Falcone M. Huerta Uribe A. Zhang T. Athineos D. Pietzke M. et al.Immune-regulated Ido1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.Mol. Cell. 2021; 81: 2290-2302.e7Google Scholar). In the main branch of the Kyn pathway, Kyn is converted into 3-hydroxykynurenine (3HK) by kynurenine monooxygenase (KMO) and further into 3-hydroxyanthranilic acid (3HAA) by kynureninase (KYNU). Subsequently, 3-hydroxyanthranilate-3,4-dioxygenase (HAAO) generates 2-amino-3-carboxymuconic semialdehyde (2ACS) from 3HAA, which can spontaneously cyclize to quinolinic acid (QA), or can be converted into picolinic acid or glutaryl-CoA. Glutaryl-CoA feeds into the Krebs cycle, whereas QA is the main substrate for NAD+ de novo synthesis (13Covarrubias A.J. Perrone R. Grozio A. Verdin E. NAD(+) metabolism and its roles in cellular processes during ageing.Nat. Rev. Mol. Cell Biol. 2021; 22: 119-141Google Scholar). In another branch of the Kyn pathway, Kyn can be converted to kynurenic acid (KynA) by Kyn aminotransferase (KAT) isoenzymes (15Badawy A.A. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects.Int. J. Tryptophan Res. 2017; 101178646917691938Google Scholar). Kyn and KynA are endogenous ligands of the aryl hydrocarbon receptor (AhR), a key ligand-activated transcription factor involved in a multitude of physiological functions including immune regulation (17Gutierrez-Vazquez C. Quintana F.J. Regulation of the immune response by the aryl hydrocarbon receptor.Immunity. 2018; 48: 19-33Google Scholar), which is discussed in detail later. A notable aspect of the Kyn pathway is that KYNU and all KAT isozymes require pyridoxyl 5′-phosphate (active vitamin B6) as a cofactor (15Badawy A.A. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects.Int. J. Tryptophan Res. 2017; 101178646917691938Google Scholar), suggesting pyridoxyl 5′-phosphate availability in microenvironments could play a role in regulating the output of the different branches of the Kyn pathway. Overall, by catalyzing the rate-limiting reaction of the Kyn pathway, IDO1 can modulate tryptophan availability, the emergence of Kyn metabolites, NAD+ biosynthesis, and fuels different metabolic pathways with tryptophan-derived carbon units. The relative expression of each enzyme of the Kyn pathway, in conjunction with substrate availability, will ultimately determine metabolic flux and the final generation of key products. Therefore, the relative expression of Kyn pathway enzymes within single cells may be highly relevant and thus appears to be an underexplored aspect of tryptophan metabolism. Besides IDO1, two other enzymes can catalyze the first reaction of the Kyn pathway, TDO2 and IDO2, a homolog of IDO1. The genes encoding IDO1 and IDO2 are located in a tandem arrangement, suggesting they may have evolved from a common ancestral gene (18Yuasa H.J. Ball H.J. Ho Y.F. Austin C.J. Whittington C.M. Belov K. et al.Characterization and evolution of vertebrate indoleamine 2, 3-dioxygenases IDOs from monotremes and marsupials.Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2009; 153: 137-144Google Scholar, 19Metz R. Duhadaway J.B. Kamasani U. Laury-Kleintop L. Muller A.J. Prendergast G.C. Novel tryptophan catabolic enzyme Ido2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan.Cancer Res. 2007; 67: 7082-7087Google Scholar). However, compared to IDO1, IDO2 exhibits a much lower catalytic activity (Km 500–1000 fold lower) (18Yuasa H.J. Ball H.J. Ho Y.F. Austin C.J. Whittington C.M. Belov K. et al.Characterization and evolution of vertebrate indoleamine 2, 3-dioxygenases IDOs from monotremes and marsupials.Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2009; 153: 137-144Google Scholar). Because of the limited information about IDO2 in the context of immunoregulation (20Mondanelli G. Mandarano M. Belladonna M.L. Suvieri C. Pelliccia C. Bellezza G. et al.Current challenges for Ido2 as target in cancer immunotherapy.Front. Immunol. 2021; 12679953Google Scholar, 21Merlo L.M.F. Peng W. DuHadaway J.B. Montgomery J.D. Prendergast G.C. Muller A.J. et al.The immunomodulatory enzyme Ido2 mediates autoimmune arthritis through a nonenzymatic mechanism.J. Immunol. 2022; 208: 571-581Google Scholar), we do not focus on this isoenzyme in this review. TDO2 is mainly expressed in the liver where it is responsible for ∼90% of nutritional tryptophan metabolism (15Badawy A.A. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects.Int. J. Tryptophan Res. 2017; 101178646917691938Google Scholar). However, TDO2 expression in different cancer types (notably gliomas) is associated with tumor immune resistance (22Ye Z. Yue L. Shi J. Shao M. Wu T. Role of Ido and TDO in cancers and related diseases and the therapeutic implications.J. Cancer. 2019; 10: 2771-2782Google Scholar). Besides IDO1, the secreted L-amino acid oxidase (LAAO) IL4i1 is another regulated tryptophan-metabolizing enzyme expressed in immune cells and associated with the regulation of immune responses (Fig. 1A). IL4i1 was first described in 1997 (23Chu C.C. Paul W.E. Fig1, an interleukin 4-induced mouse B cell gene isolated by cDNA representational difference analysis.Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2507-2512Google Scholar) as an IL-4-inducible gene in murine B cells. We now know that the main producers of IL4i1 are myeloid cells, especially macrophages and dendritic cells (DCs) (24Marquet J. Lasoudris F. Cousin C. Puiffe M.L. Martin-Garcia N. Baud V. et al.Dichotomy between factors inducing the immunosuppressive enzyme IL-4-induced gene 1 (IL4I1) in B lymphocytes and mononuclear phagocytes.Eur. J. Immunol. 2010; 40: 2557-2568Google Scholar), which we discuss extensively below. In many respects, IL4i1 is an unfortunate name as it is often confused with IL-4 and the IL-4 receptor. Moreover, the name is peripherally linked to its expression since factors other than IL-4 can control IL4i1 expression, and the protein's function as an amino acid oxidase is not indicated. By contrast, the IL4i1 relatives in snake venoms, which provided us with a key clue about mammalian IL4i1 function (25Zeitler L. Fiore A. Meyer C. Russier M. Zanella G. Suppmann S. et al.Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.Elife. 2021; 10e64806Google Scholar), describe the function of the enzyme as they are called LAAOs. Nevertheless, IL4i1 is the official name of the protein and gene in mammals. By contrast to IDO1, IL4i1 additionally metabolizes phenylalanine and tyrosine (12Boulland M.L. Marquet J. Molinier-Frenkel V. Moller P. Guiter C. Lasoudris F. et al.Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation.Blood. 2007; 110: 220-227Google Scholar, 25Zeitler L. Fiore A. Meyer C. Russier M. Zanella G. Suppmann S. et al.Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.Elife. 2021; 10e64806Google Scholar, 26Sadik A. Somarribas Patterson L.F. Ozturk S. Mohapatra S.R. Panitz V. Secker P.F. et al.IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression.Cell. 2020; 182: 1252-1270.e34Google Scholar, 27Mason J.M. Naidu M.D. Barcia M. Porti D. Chavan S.S. Chu C.C. IL-4-induced gene-1 is a leukocyte L-amino acid oxidase with an unusual acidic pH preference and lysosomal localization.J. Immunol. 2004; 173: 4561-4567Google Scholar). In fact, IL4i1 shows the highest substrate affinity towards phenylalanine (12Boulland M.L. Marquet J. Molinier-Frenkel V. Moller P. Guiter C. Lasoudris F. et al.Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation.Blood. 2007; 110: 220-227Google Scholar, 27Mason J.M. Naidu M.D. Barcia M. Porti D. Chavan S.S. Chu C.C. IL-4-induced gene-1 is a leukocyte L-amino acid oxidase with an unusual acidic pH preference and lysosomal localization.J. Immunol. 2004; 173: 4561-4567Google Scholar). Nevertheless, studies by us and others suggest that tryptophan metabolism is central for downstream cellular effects mediated by IL4i1-dependent amino acid metabolism (25Zeitler L. Fiore A. Meyer C. Russier M. Zanella G. Suppmann S. et al.Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.Elife. 2021; 10e64806Google Scholar, 26Sadik A. Somarribas Patterson L.F. Ozturk S. Mohapatra S.R. Panitz V. Secker P.F. et al.IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression.Cell. 2020; 182: 1252-1270.e34Google Scholar, 28Zhang X. Gan M. Li J. Li H. Su M. Tan D. et al.Endogenous indole pyruvate pathway for tryptophan metabolism mediated by IL4I1.J. Agric. Food Chem. 2020; 68: 10678-10684Google Scholar). IL4i1 and related LAAOs, are FAD-dependent enzymes that catalyze the oxidative deamination of L-amino acids to generate α-keto acids, hydrogen peroxide (H2O2), and ammonia (29Castellano F. Molinier-Frenkel V. An overview of l-amino acid oxidase functions from bacteria to mammals: focus on the immunoregulatory phenylalanine oxidase IL4I1.Molecules. 2017; 22: 2151Google Scholar). LAAOs occur in many different organisms including not only vertebrates but also plants, bacteria, and fungi, and gained most attention as a component of snake venoms (30Du X.Y. Clemetson K.J. Snake venom L-amino acid oxidases.Toxicon. 2002; 40: 659-665Google Scholar). Snake venom LAAOs can mediate cytotoxicity by the generation of H2O2 (31Suhr S.M. Kim D.S. Identification of the snake venom substance that induces apoptosis.Biochem. Biophys. Res. Commun. 1996; 224: 134-139Google Scholar, 32Ande S.R. Kommoju P.R. Draxl S. Murkovic M. Macheroux P. Ghisla S. et al.Mechanisms of cell death induction by L-amino acid oxidase, a major component of ophidian venom.Apoptosis. 2006; 11: 1439-1451Google Scholar, 33Burin S.M. Berzoti-Coelho M.G. Cominal J.G. Ambrosio L. Torqueti M.R. Sampaio S.V. et al.The L-amino acid oxidase from calloselasma rhodostoma snake venom modulates apoptomiRs expression in Bcr-Abl-positive cell lines.Toxicon. 2016; 120: 9-14Google Scholar, 34Costal-Oliveira F. Stransky S. Guerra-Duarte C. Naves de Souza D.L. Vivas-Ruiz D.E. Yarleque A. et al.L-amino acid oxidase from bothrops atrox snake venom triggers autophagy, apoptosis and necrosis in normal human keratinocytes.Sci. Rep. 2019; 9: 781Google Scholar). When we compared the enzymatic activity of recombinant mammalian IL4i1 with the Indian cobra (Naja naja) venom LAAO, we found that IL4i1 has a lower enzymatic activity and was not sufficient to generate toxic amounts of H2O2 (25Zeitler L. Fiore A. Meyer C. Russier M. Zanella G. Suppmann S. et al.Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.Elife. 2021; 10e64806Google Scholar). Besides the production of H2O2 and ammonia, IL4i1-mediated catabolism of the aromatic amino acids phenylalanine, tyrosine, and tryptophan produces the α-keto acids phenylpyruvate (PP), 4-hydroxyphenylpyruvate (4HPP), and indole-3-pyruvate (I3P), respectively (12Boulland M.L. Marquet J. Molinier-Frenkel V. Moller P. Guiter C. Lasoudris F. et al.Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation.Blood. 2007; 110: 220-227Google Scholar, 25Zeitler L. Fiore A. Meyer C. Russier M. Zanella G. Suppmann S. et al.Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.Elife. 2021; 10e64806Google Scholar, 26Sadik A. Somarribas Patterson L.F. Ozturk S. Mohapatra S.R. Panitz V. Secker P.F. et al.IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression.Cell. 2020; 182: 1252-1270.e34Google Scholar). Out of these metabolites, I3P from tryptophan has the greatest downstream physiological effects including activation of the AhR and anti-oxidative properties (25Zeitler L. Fiore A. Meyer C. Russier M. Zanella G. Suppmann S. et al.Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.Elife. 2021; 10e64806Google Scholar). As IL4i1 is secreted, I3P generation from tryptophan occurs in the extracellular space and requires subsequent import into cells (Fig. 1B). However, in contrast to the well-resolved Kyn pathway, little is known about the downstream metabolism of I3P, which was recently reported to give rise to KynA, indole-3-acetic acid (I3AA), indole-3-aldehyde (I3A) and indole-3-lactate (I3L) (26Sadik A. Somarribas Patterson L.F. Ozturk S. Mohapatra S.R. Panitz V. Secker P.F. et al.IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression.Cell. 2020; 182: 1252-1270.e34Google Scholar). In most (non-transformed) cells, baseline IDO1 expression is negligible. Instead, IDO1 expression is highly inducible. After stimulation with type 1 or type 2 interferons (IFNs), especially IFN-γ, IDO1 transcript amounts are induced thousands of fold above baseline via STAT1 signaling (35Fiore A. Murray P.J. Tryptophan and indole metabolism in immune regulation.Curr. Opin. Immunol. 2021; 70: 7-14Google Scholar, 36Fiore A. Zeitler L. Russier M. Gross A. Hiller M.K. Parker J.L. et al.Kynurenine importation by SLC7A11 propagates anti-ferroptotic signaling.Mol. Cell. 2022; 82: 920-932.e927Google Scholar, 37Chon S.Y. Hassanain H.H. Pine R. Gupta S.L. Involvement of two regulatory elements in interferon-gamma-regulated expression of human indoleamine 2,3-dioxygenase gene.J. Interferon Cytokine Res. 1995; 15: 517-526Google Scholar, 38Du M.X. Sotero-Esteva W.D. Taylor M.W. Analysis of transcription factors regulating induction of indoleamine 2,3-dioxygenase by IFN-gamma.J. Interferon Cytokine Res. 2000; 20: 133-142Google Scholar). Thus, since any cell that responds to IFN-γ will also express IDO1, cell-type effects of IDO1 can be difficult to tease apart. Depending on the cell system analyzed, the effects of IDO1 on local tryptophan metabolism may be underestimated (39Desvignes L. Ernst J.D. Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis.Immunity. 2009; 31: 974-985Google Scholar). A different aspect of IDO1 expression centers on cancer biology, where some tumor types (especially ovarian and endometrial tumors) express IDO1. This property can be readily observed in single-cell RNA sequencing (scRNAseq) datasets and is a foundational concept behind the use of IDO1 inhibitors in cancer therapy (40Van den Eynde B.J. Van Baren N. Baurain J.F. Is there a clinical future for Ido1 inhibitors after the failure of epacadostat in melanoma?.Annu. Rev. Cancer Biol. 2020; 4: 241-256.10Google Scholar). IDO1 inhibitors may restore anti-tumor immunity, which is blocked by a tryptophan-deficient milieu resulting from IDO1+ myeloid cells and IDO1 expressing tumor cells. A key question about tumor-specific IDO1 expression centers on its transcriptional regulation since the involvement of IFN-independent pathways driving IDO1 expression may open up new opportunities of manipulating tryptophan metabolism in the tumor microenvironment (TME) (41Hennequart M. Pilotte L. Cane S. Hoffmann D. Stroobant V. Plaen E. et al.Constitutive Ido1 expression in human tumors is driven by cyclooxygenase-2 and mediates intrinsic immune resistance cancer.Immunol. Res. 2017; 5: 695-709Google Scholar, 42Theate I. van Baren N. Pilotte L. Moulin P. Larrieu P. Renauld J.C. et al.Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues cancer.Immunol. Res. 2015; 3: 161-172Google Scholar, 43Uyttenhove C. Pilotte L. Theate I. Stroobant V. Colau D. Parmentier N. et al.Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.Nat. Med. 2003; 9: 1269-1274Google Scholar). However, at this point, very little is understood about the extrinsic IFN-independent signals that control IDO1 expression in tumor cells. It is also possible that IDO1 is controlled by cell-intrinsic pathways that "hijack" IDO1 for enhanced tumor cell metabolism and survival. So far, these important questions remain largely unexplored but are vital to answer if we are to properly understand tryptophan metabolism in cancer. IL4i1 is expressed in monocyte-derived DCs (12Boulland M.L. Marquet J. Molinier-Frenkel V. Moller P. Guiter C. Lasoudris F. et al.Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation.Blood. 2007; 110: 220-227Google Scholar), macrophages residing in granulomas (24Marquet J. Lasoudris F. Cousin C. Puiffe M.L. Martin-Garcia N. Baud V. et al.Dichotomy between factors inducing the immunosuppressive enzyme IL-4-induced gene 1 (IL4I1) in B lymphocytes and mononuclear phagocytes.Eur. J. Immunol. 2010; 40: 2557-2568Google Scholar), tumor-associated macrophages (TAMs) (44Carbonnelle-Puscian A. Copie-Bergm
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