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Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer

Abstract

Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells and myeloid-derived suppressor cells, and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small-molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in gastrointestinal stromal tumors has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer.

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Abbreviations

1MT:

1-Methyl-tryptophan

AhR:

Aryl hydrocarbon receptor (kynurenine receptor)

CCL-2:

Myeloid attraction cytokine (also known as MCP-1) which binds to receptors CCR2 and CCR4 and causes basophils and mast cells to release their granules

eIF-2α:

Master regulatory eukaryotic translation initiation factor

Gcn2:

Starvation-induced kinase that phosporylates and suppresses eIF-2α

GLK1:

A kinase also known as MAP4K3 that responds to amino acid sufficiency by activating mTORC1

IDO:

Indoleamine 2,3-dioxygenase (also known as IDO1)

IDO2:

Distinct gene encoding an IDO-related enyzme with weaker tryptophan catabolic activity

IFN-γ:

Interferon-γ

MDSC:

Myeloid-derived suppressor cells

INCB024360:

A specific small-molecule inhibitor of IDO1 enzymatic activity in clinical trials

Indoximod:

D racemer of 1-methyl-tryptophan (D-1MT), an IDO pathway inhibitor in clinical trials that relieves IDO-mediated suppression of the mTORC1 pathway (also known as NLG8189)

mTORC1:

Mammalian target of rapamycin complex-1, a master cell growth regulatory kinase

NLG919:

A specific small-molecule inhibitor of IDO1 enzymatic activity in clinical trials

NK:

Natural killer immune cells

PGE-2:

Pro-inflammatory prostaglandin produced by activation of COX-2 which may rely on IDO function for its pro-cancerous activity

PKC-θ:

Protein kinase C variant that phosphorylates and limits the function of the T cell receptor

TDLN:

Tumor-draining lymph node

TLR:

Toll-like receptor (infection/inflammation-associated PAMP receptor)

TGF-β:

Transforming growth factor-β

TPA:

12-O-tetradecanoylphorbol-13-acetate (pro-inflammatory chemical also known as PMA)

Treg:

T regulatory cells

References

  1. Prendergast GC, Jaffee EM (2007) Cancer immunologists and cancer biologists: why we didn’t talk then but need to now. Cancer Res 67(8):3500–3504

    CAS  PubMed  Google Scholar 

  2. Prendergast GC (2012) Immunological thought in the mainstream of cancer research: past divorce, recent remarriage and elective affinities of the future. Oncoimmunology 1(6):793–797. doi:10.4161/onci.20909

    PubMed Central  PubMed  Google Scholar 

  3. Prendergast GC, Jaffee EM (eds) (2013) Cancer immunotherapy: immune suppression and tumor growth, 2nd edn. Academic Press, New York

    Google Scholar 

  4. Muller AJ, Prendergast GC (2005) Marrying immunotherapy with chemotherapy: why say IDO? Cancer Res 65(18):8065–8068

    CAS  PubMed  Google Scholar 

  5. Muller AJ, DuHadaway JB, Sutanto-Ward E, Donover PS, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunomodulatory target of the tumor suppressor gene Bin1, potentiates cancer chemotherapy. Nature Med 11:312–319

    CAS  PubMed  Google Scholar 

  6. Muller AJ, Scherle PA (2006) Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat Rev Cancer 6(8):613–625

    CAS  PubMed  Google Scholar 

  7. Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67(2):792–801

    CAS  PubMed  Google Scholar 

  8. Prendergast GC (2008) Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 27(28):3889–3900. doi:10.1038/onc.2008.35

    CAS  PubMed  Google Scholar 

  9. Muller AJ, DuHadaway JB, Chang MY, Ramalingam A, Sutanto-Ward E, Boulden J, Soler AP, Mandik-Nayak L, Gilmour SK, Prendergast GC (2010) Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion. Cancer Immunol Immunother 59(11):1655–1663. doi:10.1007/s00262-010-0891-4

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Smith C, Chang MY, Parker KH, Beury DW, Duhadaway JB, Flick HE, Boulden J, Sutanto-Ward E, Soler AP, Laury-Kleintop LD, Mandik-Nayak L, Metz R, Ostrand-Rosenberg S, Prendergast GC, Muller AJ (2012) IDO Is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov 2(8):722–735. doi:10.1158/2159-8290.CD-12-0014

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Boyland E, Williams DC (1956) The metabolism of tryptophan. 2. The metabolism of tryptophan in patients suffering from cancer of the bladder. Biochem J 64(3):578–582

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Yoshida R, Imanishi J, Oku T, Kishida T, Hayaishi O (1981) Induction of pulmonary indoleamine 2,3-dioxygenase by interferon. Proc Natl Acad Sci USA 78(1):129–132

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193

    CAS  PubMed  Google Scholar 

  14. Mellor AL, Munn DH (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 20:469–473

    CAS  PubMed  Google Scholar 

  15. Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117(5):1147–1154

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, Fioretti MC, Puccetti P (2002) T cell apoptosis by tryptophan catabolism. Cell Death Differ 9:1069–1077

    CAS  PubMed  Google Scholar 

  17. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB (2002) Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 196(4):459–468

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Terness P, Bauer TM, Rose L, Dufter C, Watzlik A, Simon H, Opelz G (2002) Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196(4):447–457

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, Moretta L, Moretta A, Vitale M (2006) The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood 108(13):4118–4125. doi:10.1182/blood-2006-03-006700

    CAS  PubMed  Google Scholar 

  20. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, Puccetti P (2003) Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4(12):1206–1212

    CAS  PubMed  Google Scholar 

  21. Mellor AL, Munn DH (2008) Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat Rev Immunol 8(1):74–80

    CAS  PubMed  Google Scholar 

  22. Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop LD, Metz R, Muller AJ (2014) IDO in inflammatory programming and immune suppression in cancer. In: Gabrilovich DI, Hurwitz AA (eds) Tumor-induced immune suppression. Springer, New York

    Google Scholar 

  23. Grohmann U, Fallarino F, Puccetti P (2003) Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol 24(5):242–248

    CAS  PubMed  Google Scholar 

  24. Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4(10):762–774

    CAS  PubMed  Google Scholar 

  25. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P (2006) 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 176(11):6752–6761

    CAS  PubMed  Google Scholar 

  26. Katz JB, Muller AJ, Metz R, Prendergast GC (2008) Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev 222:206–221. doi:10.1111/j.1600-065X.2008.00610.x

    CAS  PubMed  Google Scholar 

  27. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van Den Eynde BJ (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9(10):1269–1274

    CAS  PubMed  Google Scholar 

  28. Liu X, Newton RC, Friedman SM, Scherle PA (2009) Indoleamine 2,3-dioxygenase, an emerging target for anti-cancer therapy. Curr Cancer Drug Targets 9(8):938–952

    CAS  PubMed  Google Scholar 

  29. Prendergast GC, Muller AJ, Ramalingam A, Chang MY (2009) BAR the door: cancer suppression by amphiphysin-like genes. Biochim Biophys Acta 1795(1):25–36. doi:10.1016/j.bbcan.2008.09.001

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Ge K, DuHadaway J, Du W, Herlyn M, Rodeck U, Prendergast GC (1999) Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma. Proc Natl Acad Sci USA 96:9689–9694

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Pineda-Lucena A, Ho CS, Mao DY, Sheng Y, Laister RC, Muhandiram R, Lu Y, Seet BT, Katz S, Szyperski T, Penn LZ, Arrowsmith CH (2005) A structure-based model of the c-Myc/Bin1 protein interaction shows alternative splicing of Bin1 and c-Myc phosphorylation are key binding determinants. J Mol Biol 351(1):182–194

    CAS  PubMed  Google Scholar 

  32. Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR (2007) The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 14(3):185–193. doi:10.1038/nsmb1209

    CAS  PubMed  Google Scholar 

  33. Anczukow O, Rosenberg AZ, Akerman M, Das S, Zhan L, Karni R, Muthuswamy SK, Krainer AR (2012) The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol 19(2):220–228. doi:10.1038/nsmb.2207

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Golan-Gerstl R, Cohen M, Shilo A, Suh SS, Bakacs A, Coppola L, Karni R (2011) Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma. Cancer Res 71(13):4464–4472. doi:10.1158/0008-5472.CAN-10-4410

    CAS  PubMed  Google Scholar 

  35. Barekati Z, Radpour R, Lu Q, Bitzer J, Zheng H, Toniolo P, Lenner P, Zhong XY (2012) Methylation signature of lymph node metastases in breast cancer patients. BMC Cancer 12:244. doi:10.1186/1471-2407-12-244

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Radpour R, Barekati Z, Kohler C, Lv Q, Burki N, Diesch C, Bitzer J, Zheng H, Schmid S, Zhong XY (2011) Hypermethylation of tumor suppressor genes involved in critical regulatory pathways for developing a blood-based test in breast cancer. PLoS ONE 6(1):e16080. doi:10.1371/journal.pone.0016080

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Radpour R, Kohler C, Haghighi MM, Fan AX, Holzgreve W, Zhong XY (2009) Methylation profiles of 22 candidate genes in breast cancer using high-throughput MALDI-TOF mass array. Oncogene 28(33):2969–2978. doi:10.1038/onc.2009.149

    CAS  PubMed  Google Scholar 

  38. Kuznetsova EB, Kekeeva TV, Larin SS, Zemlyakova VV, Khomyakova AV, Babenko OV, Nemtsova MV, Zaletayev DV, Strelnikov VV (2007) Methylation of the BIN1 gene promoter CpG island associated with breast and prostate cancer. J Carcinog 6:9. doi:10.1186/1477-3163-6-9

    PubMed Central  PubMed  Google Scholar 

  39. McKenna ES, Tamayo P, Cho YJ, Tillman EJ, Mora-Blanco EL, Sansam CG, Koellhoffer EC, Pomeroy SL, Roberts CW (2012) Epigenetic inactivation of the tumor suppressor BIN1 drives proliferation of SNF5-deficient tumors. Cell Cycle 11(10):1956–1965. doi:10.4161/cc.20280

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Muller AJ, Sharma MD, Chandler PR, Duhadaway JB, Everhart ME, Johnson BA 3rd, Kahler DJ, Pihkala J, Soler AP, Munn DH, Prendergast GC, Mellor AL (2008) Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc Natl Acad Sci USA 105(44):17073–17078. doi:10.1073/pnas.0806173105

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Prendergast GC, Metz R, Muller AJ (2010) Towards a genetic definition of cancer-associated inflammation: role of the IDO pathway. Am J Pathol 176(5):2082–2087. doi:10.2353/ajpath.2010.091173

    PubMed Central  PubMed  Google Scholar 

  42. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137–148

    CAS  PubMed  Google Scholar 

  43. Willimsky G, Czeh M, Loddenkemper C, Gellermann J, Schmidt K, Wust P, Stein H, Blankenstein T (2008) Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness. J Exp Med 205(7):1687–1700. doi:10.1084/jem.20072016

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Levina V, Su Y, Gorelik E (2012) Immunological and nonimmunological effects of indoleamine 2,3-dioxygenase on breast tumor growth and spontaneous metastasis formation. Clin Dev Immunol 2012:173029. doi:10.1155/2012/173029

    PubMed Central  PubMed  Google Scholar 

  45. Pertovaara M, Hasan T, Raitala A, Oja SS, Yli-Kerttula U, Korpela M, Hurme M (2007) Indoleamine 2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season. Clin Exp Immunol 150(2):274–278. doi:10.1111/j.1365-2249.2007.03480.x

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Schroecksnadel K, Winkler C, Duftner C, Wirleitner B, Schirmer M, Fuchs D (2006) Tryptophan degradation increases with stage in patients with rheumatoid arthritis. Clin Rheumatol 25(3):334–337. doi:10.1007/s10067-005-0056-6

    PubMed  Google Scholar 

  47. Mandik-Nayak L, Allen PM (2005) Initiation of an autoimmune response: insights from a transgenic model of rheumatoid arthritis. Immunol Res 32(1–3):5–13. doi:10.1385/IR:32:1-3:005

    CAS  PubMed  Google Scholar 

  48. Scott GN, DuHadaway J, Pigott E, Ridge N, Prendergast GC, Muller AJ, Mandik-Nayak L (2009) The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. J Immunol 182(12):7509–7517. doi:10.4049/jimmunol.0804328

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Kita H, Shiraishi Y, Watanabe K, Suda K, Ohtsuka K, Koshiishi Y, Goya T (2011) Does postoperative serum interleukin-6 influence early recurrence after curative pulmonary resection of lung cancer? Ann Thorac Cardiovasc Surg Off J Assoc Thorac Cardiovasc Surg Asia 17(5):454–460

    Google Scholar 

  50. Prendergast GC, Chang MY, Mandik-Nayak L, Metz R, Muller AJ (2011) Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases. Curr Med Chem 18(15):2257–2262. doi:10.2174/092986711795656072

    CAS  PubMed  Google Scholar 

  51. Fallarino F, Grohmann U, Puccetti P (2012) Indoleamine 2,3-dioxygenase: from catalyst to signaling function. Eur J Immunol 42(8):1932–1937. doi:10.1002/eji.201242572

    CAS  PubMed  Google Scholar 

  52. Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC, Puccetti P (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3(11):1097–1101

    CAS  PubMed  Google Scholar 

  53. Fallarino F, Bianchi R, Orabona C, Vacca C, Belladonna ML, Fioretti MC, Serreze DV, Grohmann U, Puccetti P (2004) CTLA-4-Ig activates forkhead transcription factors and protects dendritic cells from oxidative stress in nonobese diabetic mice. J Exp Med 200(8):1051–1062

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Grohmann U, Volpi C, Fallarino F, Bozza S, Bianchi R, Vacca C, Orabona C, Belladonna ML, Ayroldi E, Nocentini G, Boon L, Bistoni F, Fioretti MC, Romani L, Riccardi C, Puccetti P (2007) Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med 13(5):579–586

    CAS  PubMed  Google Scholar 

  55. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP (2013) Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med 210(7):1389–1402. doi:10.1084/jem.20130066

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Munn DH, Mellor AL (2013) Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 34(3):137–143. doi:10.1016/j.it.2012.10.001

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Mellor AL, Baban B, Chandler PR, Manlapat A, Kahler DJ, Munn DH (2005) Cutting edge: CpG oligonucleotides induce splenic CD19+ dendritic cells to acquire potent indoleamine 2,3-dioxygenase-dependent T cell regulatory functions via IFN Type 1 signaling. J Immunol 175(9):5601–5605

    CAS  PubMed  Google Scholar 

  58. Orabona C, Belladonna ML, Vacca C, Bianchi R, Fallarino F, Volpi C, Gizzi S, Fioretti MC, Grohmann U, Puccetti P (2005) Cutting edge: silencing suppressor of cytokine signaling 3 expression in dendritic cells turns CD28-Ig from immune adjuvant to suppressant. J Immunol 174(11):6582–6586

    CAS  PubMed  Google Scholar 

  59. Puccetti P (2007) On watching the watchers: IDO and type I/II IFN. Eur J Immunol 37(4):876–879

    CAS  PubMed  Google Scholar 

  60. Yuan W, Collado-Hidalgo A, Yufit T, Taylor M, Varga J (1998) Modulation of cellular tryptophan metabolism in human fibroblasts by transforming growth factor-beta: selective inhibition of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA synthetase gene expression. J Cell Physiol 177(1):174–186

    CAS  PubMed  Google Scholar 

  61. Belladonna ML, Volpi C, Bianchi R, Vacca C, Orabona C, Pallotta MT, Boon L, Gizzi S, Fioretti MC, Grohmann U, Puccetti P (2008) Cutting edge: autocrine TGF-beta sustains default tolerogenesis by IDO-competent dendritic cells. J Immunol 181(8):5194–5198

    CAS  PubMed  Google Scholar 

  62. Belladonna ML, Grohmann U, Guidetti P, Volpi C, Bianchi R, Fioretti MC, Schwarcz R, Fallarino F, Puccetti P (2006) Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO. J Immunol 177(1):130–137

    CAS  PubMed  Google Scholar 

  63. Belladonna ML, Orabona C, Grohmann U, Puccetti P (2009) TGF-beta and kynurenines as the key to infectious tolerance. Trends Mol Med 15(2):41–49. doi:10.1016/j.molmed.2008.11.006

    CAS  PubMed  Google Scholar 

  64. Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, Servillo G, Brunacci C, Calvitti M, Bicciato S, Mazza EM, Boon L, Grassi F, Fioretti MC, Fallarino F, Puccetti P, Grohmann U (2011) Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol 12(9):870–878. doi:10.1038/ni.2077

    CAS  PubMed  Google Scholar 

  65. McGaha TL, Huang L, Lemos H, Metz R, Mautino M, Prendergast GC, Mellor AL (2012) Amino acid catabolism: a pivotal regulator of innate and adaptive immunity. Immunol Rev 249(1):135–157. doi:10.1111/j.1600-065X.2012.01149.x

    CAS  PubMed  Google Scholar 

  66. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478(7368):197–203. doi:10.1038/nature10491

    CAS  PubMed  Google Scholar 

  67. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185(6):3190–3198. doi:10.4049/jimmunol.0903670

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Stevens EA, Mezrich JD, Bradfield CA (2009) The aryl hydrocarbon receptor: a perspective on potential roles in the immune system. Immunology 127(3):299–311. doi:10.1111/j.1365-2567.2009.03054.x

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC (2007) 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 67(15):7082–7087. doi:10.1158/0008-5472.CAN-07-1872

    CAS  PubMed  Google Scholar 

  70. Vogel CF, Goth SR, Dong B, Pessah IN, Matsumura F (2008) Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem Biophys Res Commun 375(3):331–335. doi:10.1016/j.bbrc.2008.07.156

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Metz R, Smith C, Duhadaway JB, Chandler P, Baban B, Merlo LM, Pigott E, Keough MP, Rust S, Mellor AL, Mandik-Nayak L, Muller AJ, Prendergast GC (2014) IDO2 is critical for IDO1-mediated T cell regulation and exerts a non-redundant function in inflammation. Int Immunol. doi:10.1093/intimm/dxt073

    PubMed  Google Scholar 

  72. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22(5):633–642

    CAS  PubMed  Google Scholar 

  73. Hu HM, Tian Q, Baer M, Spooner CJ, Williams SC, Johnson PF, Schwartz RC (2000) The C/EBP bZIP domain can mediate lipopolysaccharide induction of the proinflammatory cytokines interleukin-6 and monocyte chemoattractant protein-1. J Biol Chem 275(21):16373–16381. doi:10.1074/jbc.M910269199

    CAS  PubMed  Google Scholar 

  74. Metz R, Rust S, Duhadaway JB, Mautino MR, Munn DH, Vahanian NN, Link CJ, Prendergast GC (2012) IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology 1(9):1460–1468. doi:10.4161/onci.21716

    PubMed Central  PubMed  Google Scholar 

  75. Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D, Lui KO, Fairchild PJ, Mellor AL, Ron D, Waldmann H (2009) Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci USA 106(29):12055–12060. doi:10.1073/pnas.0903919106

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Peter C, Waldmann H, Cobbold SP (2010) mTOR signalling and metabolic regulation of T cell differentiation. Curr Opin Immunol 22(5):655–661. doi:10.1016/j.coi.2010.08.010

    CAS  PubMed  Google Scholar 

  77. Chuang HC, Lan JL, Chen DY, Yang CY, Chen YM, Li JP, Huang CY, Liu PE, Wang X, Tan TH (2011) The kinase GLK controls autoimmunity and NF-kappaB signaling by activating the kinase PKC-theta in T cells. Nat Immunol 12(11):1113–1118. doi:10.1038/ni.2121

    CAS  PubMed  Google Scholar 

  78. Baban B, Chandler P, McCool D, Marshall B, Munn DH, Mellor AL (2004) Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific. J Reprod Immunol 61(2):67–77

    CAS  PubMed  Google Scholar 

  79. Chang MY, Smith C, Duhadaway JB, Pyle JR, Boulden J, Peralta Soler A, Muller AJ, Laury-Kleintop LD, Prendergast GC (2011) Cardiac and gastrointestinal liabilities modulatory enzyme indoleamine 2,3-dioxygenase. Cancer Biol Ther 12(12):1050–1058. doi:10.4161/cbt.12.12.18142

    Google Scholar 

  80. Friberg M, Jennings R, Alsarraj M, Dessureault S, Cantor A, Extermann M, Mellor AL, Munn DH, Antonia SJ (2002) Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int J Cancer 101:151–155

    CAS  PubMed  Google Scholar 

  81. Cheever MA (2008) Twelve immunotherapy drugs that could cure cancers. Immunol Rev 222:357–368. doi:10.1111/j.1600-065X.2008.00604.x

    CAS  PubMed  Google Scholar 

  82. Lob S, Konigsrainer A, Zieker D, Brucher BL, Rammensee HG, Opelz G, Terness P (2009) IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother 58(1):153–157. doi:10.1007/s00262-008-0513-6

    PubMed  Google Scholar 

  83. Yuasa HJ, Ball HJ, Austin CJ, Hunt NH (2010) 1-l-methyltryptophan is a more effective inhibitor of vertebrate IDO2 enzymes than 1-d-methyltryptophan. Comp Biochem Physiol B Biochem Mol Biol. doi:10.1016/j.cbpb.2010.04.006

    PubMed  Google Scholar 

  84. Qian F, Liao J, Villella J, Edwards R, Kalinski P, Lele S, Shrikant P, Odunsi K (2012) Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation. Cancer Immunol Immunother. doi:10.1007/s00262-012-1265-x

    PubMed Central  Google Scholar 

  85. Merlo LM, Pigott E, Duhadaway JB, Grabler S, Metz R, Prendergast GC, Mandik-Nayak L (2014) IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. J Immunol 92(5):2082–2090. doi:10.4049/jimmunol.1303012

    Google Scholar 

  86. Lob S, Konigsrainer A, Rammensee HG, Opelz G, Terness P (2009) Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer 9(6):445–452. doi:10.1038/nrc2639

    PubMed  Google Scholar 

  87. Prendergast GC, Metz R (2012) A perspective on new immune adjuvant principles: reprogramming inflammatory states to permit clearance of cancer cells and other age-associated cellular pathologies. Oncoimmunology 1(6):924–929. doi:10.4161/onci.21358

    PubMed Central  PubMed  Google Scholar 

  88. Fu T, He Q, Sharma P (2011) The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res 71(16):5445–5454. doi:10.1158/0008-5472.CAN-11-1138

    CAS  PubMed  Google Scholar 

  89. Xie DL, Wu J, Lou YL, Zhong XP (2012) Tumor suppressor TSC1 is critical for T-cell anergy. Proc Natl Acad Sci USA 109(35):14152–14157. doi:10.1073/pnas.1119744109

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Soliman HH, Antonia S, Sullivan D, Vahanian N, Link C (2009) Overcoming tumor antigen anergy in human malignancies using the novel indeolamine 2,3-dioxygenase (IDO) enzyme inhibitor, 1-methyl-D-tryptophan (1MT). J Clin Oncol 27:15s

    Google Scholar 

  91. Malachowski WP, Metz R, Prendergast GC, Muller AJ (2005) A new cancer immunosuppression target: indoleamine 2,3-dioxygenase (IDO). A review of the IDO mechanism, inhibition, and therapeutic applications. Drugs Fut 30:897–913

    CAS  Google Scholar 

  92. Sugimoto H, Oda SI, Otsuki T, Hino T, Yoshida T, Shiro Y (2006) Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc Natl Acad Sci USA 103:2311–2316

    Google Scholar 

  93. Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, Leffet L, Hansbury MJ, Thomas B, Rupar M, Waeltz P, Bowman KJ, Polam P, Sparks RB, Yue EW, Li Y, Wynn R, Fridman JS, Burn TC, Combs AP, Newton RC, Scherle PA (2010) Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115(17):3520–3530. doi:10.1182/blood-2009-09-246124

    CAS  PubMed  Google Scholar 

  94. Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL, Haley PJ, Burn TC, Waeltz P, Sparks RB, Yue EW, Combs AP, Scherle PA, Vaddi K, Fridman JS (2010) Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther. doi:10.1158/1535-7163.MCT-09-0628

    PubMed  Google Scholar 

  95. Sorensen RB, Berge-Hansen L, Junker N, Hansen CA, Hadrup SR, Schumacher TN, Svane IM, Becker JC, thor Straten P, Andersen MH (2009) The immune system strikes back: cellular immune responses against indoleamine 2,3-dioxygenase. PLoS ONE 4(9):e6910. doi:10.1371/journal.pone.0006910

    PubMed Central  PubMed  Google Scholar 

  96. Sorensen RB, Hadrup SR, Svane IM, Hjortso MC, Thor Straten P, Andersen MH (2011) Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators. Blood 117(7):2200–2210. doi:10.1182/blood-2010-06-288498

    PubMed Central  PubMed  Google Scholar 

  97. Sorensen RB, Kollgaard T, Andersen RS, van den Berg JH, Svane IM, Straten P, Andersen MH (2011) Spontaneous cytotoxic T-Cell reactivity against indoleamine 2,3-dioxygenase-2. Cancer Res 71(6):2038–2044. doi:10.1158/0008-5472.CAN-10-3403

    CAS  PubMed  Google Scholar 

  98. Iversen TZ, Engell-Noerregaard L, Ellebaek E, Andersen R, Larsen SK, Bjoern J, Zeyher C, Gouttefangeas C, Thomsen BM, Holm B, Thor Straten P, Mellemgaard A, Andersen MH, Svane IM (2014) Long-lasting disease stabilization in the absence of toxicity in metastatic lung cancer patients vaccinated with an epitope derived from indoleamine 2,3 dioxygenase. Clin Cancer Res 20(1):221–232. doi:10.1158/1078-0432.CCR-13-1560

    CAS  PubMed  Google Scholar 

  99. Sayama S, Yoshida R, Oku T, Imanishi J, Kishida T, Hayaishi O (1981) Inhibition of interferon-mediated induction of indoleamine 2,3-dioxygenase in mouse lung by inhibitors of prostaglandin biosynthesis. Proc Natl Acad Sci USA 78(12):7327–7330

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Basu GD, Tinder TL, Bradley JM, Tu T, Hattrup CL, Pockaj BA, Mukherjee P (2006) Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO. J Immunol 177(4):2391–2402

    CAS  PubMed  Google Scholar 

  101. Lee SY, Choi HK, Lee KJ, Jung JY, Hur GY, Jung KH, Kim JH, Shin C, Shim JJ, In KH, Kang KH, Yoo SH (2009) The immune tolerance of cancer is mediated by IDO that is inhibited by COX-2 inhibitors through regulatory T cells. J Immunother 32(1):22–28. doi:10.1097/CJI.0b013e31818ac2f7

    CAS  PubMed  Google Scholar 

  102. Muller AJ, DuHadaway JB, Jaller D, Curtis P, Metz R, Prendergast GC (2010) Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. Cancer Res 70(5):1845–1853. doi:10.1158/0008-5472.CAN-09-3613

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, Sorenson EC, Popow R, Ariyan C, Rossi F, Besmer P, Guo T, Antonescu CR, Taguchi T, Yuan J, Wolchok JD, Allison JP, Dematteo RP (2011) Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 17(9):1094–1100. doi:10.1038/nm.2438

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Work in the authors’ laboratories has been supported by grants from the NIH, Department of Defense Breast and Lung Cancer Research Programs, Susan G. Komen for the Cure and the W.W. Smith Trust with additional support from NewLink Genetics Corporation, Sharpe-Strumia Foundation, Dan Green Foundation, Lankenau Medical Center Foundation and the Main Line Health System. C. Smith was the recipient of a Postdoctoral Fellowship through the US Department of Defense Breast Cancer Research Program.

Conflict of interest

G.C. Prendergast, R. Metz and A.J. Muller state a conflict of interest as shareholders and G.C. Prendergast also a grant recipient and a member of the scientific advisory board for New Link Genetics Corporation, a biopharmaceutical company that has licensed IDO intellectual property for clinical development from the Lankenau Institute of Medical Research, as described in U.S. Patents Nos. 7705022, 7714139, 8008281, 8058416, 8383613, 8389568, 8436151, 8476454 and 8586636. The other authors state no conflict of interest.

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Correspondence to George C. Prendergast.

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This paper is a Focussed Research Review based on a presentation given at the Eleventh Annual Meeting of the Association for Cancer Immunotherapy (CIMT), held in Mainz, Germany, 14th-16th May, 2013. It is part of a CII series of Focussed Research Reviews and meeting report.

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Prendergast, G.C., Smith, C., Thomas, S. et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother 63, 721–735 (2014). https://doi.org/10.1007/s00262-014-1549-4

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Keywords

  • Tryptophan catabolism
  • Immunometabolism
  • Immune escape
  • Immune surveillance
  • Immunoediting
  • Cancer-associated inflammation