Indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO) represent some of the key immune regulators. Their increased activity has been demonstrated in a number of human malignancies but not yet in chronic myeloid leukemia (CML). In the present study, the activity of these enzymes was tested in 29 CML patients and 28 healthy subjects by monitoring the kynurenine (KYN)/tryptophan ratio. Serum samples taken prior to the therapy displayed a highly significant difference in KYN levels between the patient and control groups. However, increased KYN levels were detected in only 13 (44.8%) of these CML patients. The KYN levels in pretreatment sera of the patients correlated with the tumor burden. There was also a strong correlation between KYN levels and uric acid levels (UA). This suggests but does not prove the possible involvement of UA in activating IDO family of enzymes. Whenever tested, the increased KYN levels normalized in the course of the therapy. Patients with normal KYN levels in their pretreatment sera and subsequently treated with interferon-α, showed a transitory increase in their KYN levels. The present data indicate that CML should be added to the malignancies with an increased activity of the IDO family of enzymes and suggest that IDO inhibitors may be used in the treatment of CML patients.

Department of Analytical Chemistry; Faculty of Pharmacy; Charles University ; Hradec Králové Czech Republic ; 3 Internal Gerontometabolic Clinic; University Hospital ; Hradec Králové Czech Republic

Department of Biostatistics; State Institute of Health ; Prague Czech Republic

Department of Experimental Virology; Institute of Haematology and Blood Transfusion ; Prague Czech Republic

Institute of Immunology; 1st Medical Faculty; Charles University ; Prague; Czech Republic ; Department of Immunology and Microbiology; 1st Medical Faculty; Charles University and the General Teaching Hospital Prague ; Prague Czech Republic

See more in PubMed

Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC. 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; 67:7082-7; PMID:; http://dx.doi.org/10.1158/0008-5472.CAN-07-1872 PubMed DOI

Capece L, Arrar M, Roitberg AE, Yeh SR, Marti MA, Estrin DA. Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase. Proteins 2010; 78:2961-72; PMID:; http://dx.doi.org/10.1002/prot.22819 PubMed DOI PMC

Brown RR, Ozaki Y, Datta SP, Borden EC, Sondel PM, Malone DG. Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDS. Adv. Exp. Med. Biol. 1991; 294:425-35; PMID:; http://dx.doi.org/10.1007/978-1-4684-5952-4_39 PubMed DOI

Danesch U, Gloss B, Schmid W, Schutz G, Schule R, Renkawitz R. Glucocorticoid induction of the rat tryptophan oxygenase gene is mediated by two widely separated glucocorticoid-responsive elements. EMBO J. 1987; 6:625-30; PMID: PubMed PMC

Takikawa O, Yoshida R, Kido R, Hayaishi O. Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J. Biol. Chem. 1986; 261:3648-53; PMID: PubMed

Muller N, Schwarz MJ. Immune System and Schizophrenia. Curr. Immunol. Rev. 2010; 6:213-20; PMID:; http://dx.doi.org/10.2174/157339510791823673 PubMed DOI PMC

Dankers AC, Mutsaers HA, Dijkman HB, van den Heuvel LP, Hoenderop JG, Sweep FC, Russel FG, Masereeuw R. Hyperuricemia influences tryptophan metabolism via inhibition of multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). Biochim. Biophys. Acta 2013; 1832:1715-22; PMID:; http://dx.doi.org/10.1016/j.bbadis.2013.05.002 PubMed DOI

Mackenzie CR, Gonzalez RG, Kniep E, Roch S, Daubener W. Cytokine mediated regulation of interferon-gamma-induced IDO activation. Adv. Exp. Med. Biol. 1999; 467:533-9; PMID:; http://dx.doi.org/10.1007/978-1-4615-4709-9_66 PubMed DOI

Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998; 281:1191-3; PMID:; http://dx.doi.org/10.1126/science.281.5380.1191 PubMed DOI

Blaschitz A, Gauster M, Fuchs D, Lang I, Maschke P, Ulrich D, Karpf E, Takikawa O, Schimek MG, Dohr G, et al. Vascular endothelial expression of indoleamine 2,3-dioxygenase 1 forms a positive gradient towards the feto-maternal interface. PLoS. One. 2011; 6:e21774; PMID:; http://dx.doi.org/10.1371/journal.pone.0021774 PubMed DOI PMC

Fallarino F, Volpi C, Zelante T, Vacca C, Calvitti M, Fioretti MC, Puccetti P, Romani L, Grohmann U. IDO mediates TLR9-driven protection from experimental autoimmune diabetes. J. Immunol. 2009; 183:6303-12; PMID:; http://dx.doi.org/10.4049/jimmunol.0901577 PubMed DOI

Ozaki Y, Edelstein MP, Duch DS. Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. Proc. Natl. Acad. Sci. U. S. A 1988; 85:1242-6; PMID:; http://dx.doi.org/10.1073/pnas.85.4.1242 PubMed DOI PMC

Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, Puccetti P. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 2003; 4:1206-12; PMID:; http://dx.doi.org/10.1038/ni1003 PubMed DOI

Prendergast GC. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 2008; 27:3889-900; PMID:; http://dx.doi.org/10.1038/onc.2008.35 PubMed DOI

Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol. 2009; 183:2475-83; PMID:; http://dx.doi.org/10.4049/jimmunol.0900986 PubMed DOI PMC

Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 2010; 185:3190-8; PMID:; http://dx.doi.org/10.4049/jimmunol.0903670 PubMed DOI PMC

Munn DH. Indoleamine 2,3-dioxygenase, Tregs and cancer. Curr. Med. Chem. 2011; 18:2240-6; PMID:; http://dx.doi.org/10.2174/092986711795656045 PubMed DOI

Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 2006; 176:6752-61; PMID:; http://dx.doi.org/10.4049/jimmunol.176.11.6752 PubMed DOI

Mellor AL, Baban B, Chandler P, Marshall B, Jhaver K, Hansen A, Koni PA, Iwashima M, Munn DH. Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J. Immunol. 2003; 171:1652-5; PMID:; http://dx.doi.org/10.4049/jimmunol.171.4.1652 PubMed DOI

Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, Fioretti MC, Puccetti P. T cell apoptosis by tryptophan catabolism. Cell Death. Differ. 2002; 9:1069-77; PMID:; http://dx.doi.org/10.1038/sj.cdd.4401073 PubMed DOI

Song H, Park H, Kim J, Park G, Kim YS, Kim SM, Kim D, Seo SK, Lee HK, Cho D, et al. IDO metabolite produced by EBV-transformed B cells inhibits surface expression of NKG2D in NK cells via the c-Jun N-terminal kinase (JNK) pathway. Immunol. Lett. 2011; 136:187-93; PMID:; http://dx.doi.org/10.1016/j.imlet.2011.01.009 PubMed DOI

Witkiewicz AK, Costantino CL, Metz R, Muller AJ, Prendergast GC, Yeo CJ, Brody JR. Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J. Am. Coll. Surg. 2009; 208:781-7; PMID:; http://dx.doi.org/10.1016/j.jamcollsurg.2008.12.018 PubMed DOI PMC

Pilotte L, Larrieu P, Stroobant V, Colau D, Dolusic E, Frederick R, De PE, Uyttenhove C, Wouters J, Masereel B, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl. Acad. Sci. U. S. A 2012; 109:2497-502; PMID:; http://dx.doi.org/10.1073/pnas.1113873109 PubMed DOI PMC

Lee JR, Dalton RR, Messina JL, Sharma MD, Smith DM, Burgess RE, Mazzella F, Antonia SJ, Mellor AL, Munn DH. Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma. Lab Invest 2003; 83:1457-66; PMID:; http://dx.doi.org/10.1097/01.LAB.0000090158.68852.D1 PubMed DOI

Weinlich G, Murr C, Richardsen L, Winkler C, Fuchs D. Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients. Dermatology 2007; 214:8-14; PMID:; http://dx.doi.org/10.1159/000096906 PubMed DOI

Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, Werner ER, Werner-Felmayer G, Weiss HG, Gobel G, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin. Cancer Res. 2006; 12:1144-51; PMID:; http://dx.doi.org/10.1158/1078-0432.CCR-05-1966 PubMed DOI

Curti A, Aluigi M, Pandolfi S, Ferri E, Isidori A, Salvestrini V, Durelli I, Horenstein AL, Fiore F, Massaia M, et al. Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. Leukemia 2007; 21:353-5; PMID:; http://dx.doi.org/10.1038/sj.leu.2404485 PubMed DOI

Pan K, Wang H, Chen MS, Zhang HK, Weng DS, Zhou J, Huang W, Li JJ, Song HF, Xia JC. Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 2008; 134:1247-53; PMID:; http://dx.doi.org/10.1007/s00432-008-0395-1 PubMed DOI

Feder-Mengus C, Wyler S, Hudolin T, Ruszat R, Bubendorf L, Chiarugi A, Pittelli M, Weber WP, Bachmann A, Gasser TC, et al. High expression of indoleamine 2,3-dioxygenase gene in prostate cancer. Eur. J. Cancer 2008; 44:2266-75; PMID:; http://dx.doi.org/10.1016/j.ejca.2008.05.023 PubMed DOI

Urakawa H, Nishida Y, Nakashima H, Shimoyama Y, Nakamura S, Ishiguro N. Prognostic value of indoleamine 2,3-dioxygenase expression in high grade osteosarcoma. Clin. Exp. Metastasis 2009; 26:1005-12; PMID:; http://dx.doi.org/10.1007/s10585-009-9290-7 PubMed DOI

Suzuki Y, Suda T, Furuhashi K, Suzuki M, Fujie M, Hahimoto D, Nakamura Y, Inui N, Nakamura H, Chida K. Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer 2010; 67:361-5; PMID:; http://dx.doi.org/10.1016/j.lungcan.2009.05.001 PubMed DOI

de Jong RA, Nijman HW, Boezen HM, Volmer M, Ten Hoor KA, Krijnen J, van der Zee AG, Hollema H, Kema IP. Serum tryptophan and kynurenine concentrations as parameters for indoleamine 2,3-dioxygenase activity in patients with endometrial, ovarian, and vulvar cancer. Int. J. Gynecol. Cancer 2011; 21:1320-7; PMID: PubMed

Bonanno G, Mariotti A, Procoli A, Folgiero V, Natale D, De RL, Majolino I, Novarese L, Rocci A, Gambella M, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. J. Transl. Med. 2012; 10:247; PMID:; http://dx.doi.org/10.1186/1479-5876-10-247 PubMed DOI PMC

Lindstrom V, Aittoniemi J, Jylhava J, Eklund C, Hurme M, Paavonen T, Oja SS, Itala-Remes M, Sinisalo M. Indoleamine 2,3-dioxygenase activity and expression in patients with chronic lymphocytic leukemia. Clin. Lymphoma Myeloma. Leuk. 2012; 12:363-5; PMID:; http://dx.doi.org/10.1016/j.clml.2012.06.001 PubMed DOI

Mitsuka K, Kawataki T, Satoh E, Asahara T, Horikoshi T, Kinouchi H. Expression of indoleamine 2,3-dioxygenase and correlation with pathological malignancy in gliomas. Neurosurgery 2013; 72:1031-8; PMID:; http://dx.doi.org/10.1227/NEU.0b013e31828cf945 PubMed DOI

Choe JY, Yun JY, Jeon YK, Kim SH, Park G, Huh JR, Oh S, Kim JE. Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: a retrospective cohort study. BMC. Cancer 2014; 14:335; PMID:; http://dx.doi.org/10.1186/1471-2407-14-335 PubMed DOI PMC

Ye J, Liu H, Hu Y, Li P, Zhang G, Li Y. Tumoral indoleamine 2,3-dioxygenase expression predicts poor outcome in laryngeal squamous cell carcinoma. Virchows Arch. 2013; 462:73-81; PMID:; http://dx.doi.org/10.1007/s00428-012-1340-x PubMed DOI

Vonka V. Immunotherapy of chronic myeloid leukemia: present state and future prospects. Immunotherapy. 2010; 2:227-41; PMID:; http://dx.doi.org/10.2217/imt.10.2 PubMed DOI

Vonka V. Comments on therapeutic cancer vaccines. Immunotherapy. 2012; 4:133-5; PMID:; http://dx.doi.org/10.2217/imt.11.173 PubMed DOI

Awad M, Pravica V, Perrey C, El GA, Yonan N, Sinnott PJ, Hutchinson IV. CA repeat allele polymorphism in the first intron of the human interferon-gamma gene is associated with lung allograft fibrosis. Hum. Immunol. 1999; 60:343-6; PMID:; http://dx.doi.org/10.1016/S0198-8859(98)00133-5 PubMed DOI

Sorensen RB, Hadrup SR, Svane IM, Hjortso MC, Thor SP, Andersen MH. Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators. Blood 2011; 117:2200-10; PMID:; http://dx.doi.org/10.1182/blood-2010-06-288498 PubMed DOI PMC

Munir S, Larsen SK, Iversen TZ, Donia M, Klausen TW, Svane IM, Straten PT, Andersen MH. Natural CD4+ T-cell responses against indoleamine 2,3-dioxygenase. PLoS. One. 2012; 7:e34568; PMID:; http://dx.doi.org/10.1371/journal.pone.0034568 PubMed DOI PMC

Sorensen RB, Kollgaard T, Andersen RS, van den Berg JH, Svane IM, Straten P, Andersen MH. Spontaneous cytotoxic T-Cell reactivity against indoleamine 2,3-dioxygenase-2. Cancer Res. 2011; 71:2038-44; PMID:; http://dx.doi.org/10.1158/0008-5472.CAN-10-3403 PubMed DOI

Fotopoulou C, Sehouli J, Pschowski R, VON HS, Domanska G, Braicu EI, Fusch G, Reinke P, Schefold JC. Systemic changes of tryptophan catabolites via the indoleamine-2,3-dioxygenase pathway in primary cervical cancer. Anticancer Res. 2011; 31:2629-35; PMID: PubMed

Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr. Opin. Hematol. 2001; 8:131-6; PMID:; http://dx.doi.org/10.1097/00062752-200105000-00001 PubMed DOI

Capuron L, Schroecksnadel S, Feart C, Aubert A, Higueret D, Barberger-Gateau P, Laye S, Fuchs D. Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms. Biol. Psychiatry 2011; 70:175-82; PMID:; http://dx.doi.org/10.1016/j.biopsych.2010.12.006 PubMed DOI

Humlova Z, Klamova H, Janatkova I, Sandova P, Sterzl I, Sobotkova E, Hamsikova E, Haskovec C, Pisacka M, Cetkovsky P, et al. Immunological profiles of patients with chronic myeloid leukaemia. I. State before the start of treatment. Folia Biol. (Praha) 2006; 52:47-58; PMID: PubMed

Humlova Z, Klamova H, Janatkova I, Malickova K, Kralikova P, Sterzl I, Roth Z, Hamsikova E, Vonka V. Changes of immunological profiles in patients with chronic myeloid leukemia in the course of treatment. Clin. Dev. Immunol. 2010; 2010:137320; PMID:; http://dx.doi.org/10.1155/2010/137320 PubMed DOI PMC

Curreli S, Romerio F, Mirandola P, Barion P, Bemis K, Zella D. Human primary CD4 + T cells activated in the presence of IFN-alpha 2b express functional indoleamine 2,3-dioxygenase. J. Interferon Cytokine Res. 2001; 21:431-7; PMID:; http://dx.doi.org/10.1089/107999001750277916 PubMed DOI

Nagai A, Kubota M, Tang L, Adachi S, Usami I, Matsubara K. Hyperuricemia in pediatric malignancies before treatment. Nucleosides Nucleotides Nucleic Acids 2011; 30:1060-5; PMID:; http://dx.doi.org/10.1080/15257770.2011.591745 PubMed DOI

Yamauchi T, Negoro E, Lee S, Takai M, Matsuda Y, Takagi K, Kishi S, Tai K, Hosono N, Tasaki T, et al. A high serum uric acid level is associated with poor prognosis in patients with acute myeloid leukemia. Anticancer Res. 2013; 33:3947-51; PMID: PubMed

Metz R, Rust S, Duhadaway JB, Mautino MR, Munn DH, Vahanian NN, Link CJ, Prendergast GC. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology. 2012; 1:1460-8; PMID:; http://dx.doi.org/10.4161/onci.21716 PubMed DOI PMC

Krcmova L, Solichova D, Melichar B, Kasparova M, Plisek J, Sobotka L, Solich P. Determination of neopterin, kynurenine, tryptophan and creatinine in human serum by high throuput HPLC. Talanta 2011; 85:1466-71; PMID:; http://dx.doi.org/10.1016/j.talanta.2011.06.027 PubMed DOI

Trial Watch-Small molecules targeting the immunological tumor microenvironment for cancer therapy