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IDO/TDO Inhibition in Cancer

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Oncoimmunology

Abstract

Elevated tryptophan catabolism in many human tumors occurs due to activation of indoleamine 2,3-dioxygenase-1 (IDO1) or tryptophan dioxygenase (TDO), structurally distinct enzymes which drive multifaceted processes of immunosuppression, neovascularization, and metastatic progression. Immunosuppression by IDO1 involves suppression of local CD8+ T effector cells and natural killer cells along with induction of CD4+ T regulatory cells (Treg) and myeloid-derived suppressor cells (MDSC). While less studied, TDO, like IDO1, is implicated in immune escape and metastatic progression, and emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated Treg function and perhaps contribute to B-cell inflamed states in certain cancers. IDO1 and TDO are overexpressed primarily in neoplastic cells in tumors, but they are also elevated variably in stromal, endothelial, and innate immune cells of the tumor microenvironment and in tumor-draining lymph nodes in different human cancers. Preclinical pharmacological and genetic studies validated IDO1 as a therapeutic target in cancer as combined with “immunogenic” chemotherapy or immune checkpoint modalities. Mechanistic investigations encourage the concept that IDO/TDO function is rooted in inflammatory programming, including as support for tumor neovascularization, MDSC generation, and metastasis beyond established effects on adaptive immune tolerance. Discovery and development of small-molecule enzyme inhibitors of IDO1 derived from the hydroxylamidine and phenylimidazole chemotypes have advanced furthest to date in phase II/III trials (epacadostat and GDC-0919, respectively). TDO inhibitors and second-generation “tunable” IDO/TDO inhibitors being pursued may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This chapter focuses on work from preclinical pioneers of the first bioactive IDO inhibitors as a novel class of small-molecule drugs to reprogram inflammation and degrade a key immune escape pathway in cancer.

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Abbreviations

1MT:

1-Methyl-tryptophan, a racemic mixture of L,D isoforms termed IDO pathway inhibitors, the latter of which (D-1MT) is in phase II/III clinical development now known as indoximod

AhR:

Aryl hydrocarbon receptor (kynurenine receptor)

BID:

Twice-daily dosing

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

CR:

Complete response

eIF-2α:

Master regulatory eukaryotic translation initiation factor

Gcn2:

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

GLK1:

A kinase that responds to amino acid sufficiency by activating mTORC1

IDO:

Indoleamine 2,3-dioxygenase enzyme; in older literature refers to the IDO1 gene product; in more recent literature may refer to IDO1 and IDO2 gene products which are structurally related

IDO1:

Indoleamine 2,3-dioxygenase-1 enzyme (gene nomenclature IDO1)

IDO2:

Indoleamine 2,3-dioxygenase-2 enzyme (gene nomenclature IDO2) distinct IDO-related gene product (gene nomenclature IDO2, located immediately downstream of IDO1 in the murine and human genomes)

IFN-γ:

Interferon-γ

INCB024360:

A lead small-molecule inhibitor of IDO1 enzymatic activity presently in phase II/III clinical development now known as epacadostat

Indoximod:

D racemer of 1-methyl-tryptophan (D-1MT), an IDO pathway inhibitor in clinical trials that may act at clinical dose levels by relieving IDO1-mediated suppression of the mTORC1 pathway (also known as NLG-8189)

MDSC:

Myeloid-derived suppressor cells

mTORC1:

Mammalian target of rapamycin complex-1 (master cell growth regulatory kinase)

NLG919:

A small-molecule inhibitor of IDO1 enzymatic activity in clinical trials also known as navoximod

NK:

Natural killer immune cells

ORR:

Overall response rate

PFS:

Progression-free survival

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

PR:

Partial response

SD:

Stable disease

TDLN:

Tumor-draining lymph node

TDO:

Tryptophan dioxygenase enzyme; structurally unrelated to IDO enzymes (gene nomenclature TDO2)

TDO2:

Tryptophanase dioxygenase gene nomenclature

TLR:

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

TGF-ß:

Transforming growth factor-ß

TPA:

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

Treg:

T regulatory cells

References

  1. Boyland E, Williams DC. The metabolism of tryptophan. 2. The metabolism of tryptophan in patients suffering from cancer of the bladder. Biochem J. 1956;64:578–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schwarcz R, Stone TW. The kynurenine pathway and the brain: challenges, controversies and promises. Neuropharmacology. 2017;112:237–47.

    Article  CAS  PubMed  Google Scholar 

  3. Yoshida R, Imanishi J, Oku T, Kishida T, Hayaishi O. Induction of pulmonary indoleamine 2,3-dioxygenase by interferon. Proc Natl Acad Sci U S A. 1981;78:129–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191–3.

    Article  CAS  PubMed  Google Scholar 

  5. Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today. 1999;20:469–73.

    Article  CAS  PubMed  Google Scholar 

  6. Uyttenhove 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;9:1269–74.

    Article  CAS  PubMed  Google Scholar 

  7. Theate I, van Baren N, Pilotte L, Moulin P, Larrieu P, Renauld JC, 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;3:161–72.

    Article  CAS  PubMed  Google Scholar 

  8. Muller AJ, DuHadaway JB, Sutanto-Ward E, Donover PS, Prendergast GC. Inhibition of indoleamine 2,3-dioxygenase, an immunomodulatory target of the tumor suppressor gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005;11:312–9.

    Article  CAS  PubMed  Google Scholar 

  9. Jia Y, Wang H, Wang Y, Wang T, Wang M, Ma M, et al. Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients. Int J Cancer. 2015;137:1095–106.

    Article  CAS  PubMed  Google Scholar 

  10. Ge K, DuHadaway J, Du W, Herlyn M, Rodeck U, Prendergast GC. 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 U S A. 1999;96:9689–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol. 2007;14:185–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xu Q, Lee C. Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences. Nucleic Acids Res. 2003;31:5635–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McKenna ES, Tamayo P, Cho YJ, Tillman EJ, Mora-Blanco EL, Sansam CG, et al. Epigenetic inactivation of the tumor suppressor BIN1 drives proliferation of SNF5-deficient tumors. Cell Cycle. 2012;11:1956–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Prendergast GC, Muller AJ, Ramalingam A, Chang MY. BAR the door: cancer suppression by amphiphysin-like genes. Biochim Biophys Acta. 2009;1795:25–36.

    CAS  PubMed  Google Scholar 

  15. Friberg M, Jennings R, Alsarraj M, Dessureault S, Cantor A, Extermann M, et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int J Cancer. 2002;101:151–5.

    Article  CAS  PubMed  Google Scholar 

  16. Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, et al. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. 2007;67:792–801.

    Article  CAS  PubMed  Google Scholar 

  17. Malachowski WP, Metz R, Prendergast GC, Muller AJ. A new cancer immunosuppression target: indoleamine 2,3-dioxygenase (IDO). A review of the IDO mechanism, inhibition, and therapeutic applications. Drugs Future. 2005;30:897–13.

    Article  CAS  Google Scholar 

  18. Muller AJ, Malachowski WP, Prendergast GC. Indoleamine 2,3-dioxygenase in cancer: targeting pathological immune tolerance with small-molecule inhibitors. Expert Opin Ther Targets. 2005;9:831–49.

    Article  CAS  PubMed  Google Scholar 

  19. Muller AJ, Prendergast GC. Marrying immunotherapy with chemotherapy: why say IDO? Cancer Res. 2005;65:8065–8.

    Article  CAS  PubMed  Google Scholar 

  20. Banerjee T, DuHadaway JB, Gaspari P, Sutanto-Ward E, Munn DH, Mellor AL, et al. A key in vivo antitumor mechanism of action of natural product-based brassinins is inhibition of indoleamine 2,3-dioxygenase. Oncogene. 2008;27:2851–7.

    Article  CAS  PubMed  Google Scholar 

  21. Kumar S, Jaller D, Patel B, LaLonde JM, DuHadaway JB, Malachowski WP, et al. Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase. J Med Chem. 2008;51:4968–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kumar S, Malachowski WP, DuHadaway JB, LaLonde JM, Carroll PJ, Jaller D, et al. Indoleamine 2,3-dioxygenase is the anticancer target for a novel series of potent naphthoquinone-based inhibitors. J Med Chem. 2008;51:1706–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yue EW, Douty B, Wayland B, Bower M, Liu X, Leffet L, et al. Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J Med Chem. 2009;52:7364–7.

    Article  CAS  PubMed  Google Scholar 

  24. Muller AJ, Sharma MD, Chandler PR, DuHadaway JB, Everhart ME, Johnson BA 3rd, et al. Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc Natl Acad Sci U S A. 2008;105:17073–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Smith C, Chang MY, Parker KH, Beury DW, DuHadaway JB, Flick HE, et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov. 2012;2:722–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Prendergast GC. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene. 2008;27:3889–900.

    Article  CAS  PubMed  Google Scholar 

  27. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  CAS  PubMed  Google Scholar 

  28. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  29. Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell. 2009;136:823–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137–43.

    Article  CAS  PubMed  Google Scholar 

  31. Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ, et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest. 2004;114:280–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Metz R, DuHadaway JB, Rust S, Munn DH, Muller AJ, Mautino M, et al. Zinc protoporphyrin IX stimulates tumor immunity by disrupting the immunosuppressive enzyme indoleamine 2,3-dioxygenase. Mol Cancer Ther. 2010;9:1864–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Muller AJ, Mandik-Nayak L, Prendergast GC. Beyond immunosuppression: reconsidering indoleamine 2,3-dioxygenase as a pathogenic element of chronic inflammation. Immunotherapy. 2010;2:293–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004;64:5839–49.

    Article  CAS  PubMed  Google Scholar 

  36. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010;70:68–77.

    Article  CAS  PubMed  Google Scholar 

  37. Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med. 2007;13:828–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hanson EM, Clements VK, Sinha P, Ilkovitch D, Ostrand-Rosenberg S. Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. J Immunol. 2009;183:937–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Serafini P, Mgebroff S, Noonan K, Borrello I. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res. 2008;68:5439–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007;179:977–83.

    Article  CAS  PubMed  Google Scholar 

  41. Yu J, Du W, Yan F, Wang Y, Li H, Cao S, et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol. 2013;190:3783–97.

    Article  CAS  PubMed  Google Scholar 

  42. Holmgaard RB, Zamarin D, Lesokhin A, Merghoub T, Wolchok JD. Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance to immunotherapy in indoleamine 2,3-dioxygenase-expressing tumors. EBioMedicine. 2016;6:50–8.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Holmgaard RB, Zamarin D, Li Y, Gasmi B, Munn DH, Allison JP, et al. Tumor-expressed IDO recruits and activates MDSCs in a treg-dependent manner. Cell Rep. 2015;13:412–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mougiakakos D, Jitschin R, von Bahr L, Poschke I, Gary R, Sundberg B, et al. Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation. Leukemia. 2013;27:377–88.

    Article  CAS  PubMed  Google Scholar 

  45. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–64.

    Article  CAS  PubMed  Google Scholar 

  46. Ribatti D, Vacca A, Nico B, Roncali L, Dammacco F. Postnatal vasculogenesis. Mech Dev. 2001;100:157–63.

    Article  CAS  PubMed  Google Scholar 

  47. McClintock JY, Wagner EM. Role of IL-6 in systemic angiogenesis of the lung. J Appl Physiol. 2005;99:861–6.

    Article  CAS  PubMed  Google Scholar 

  48. Gopinathan G, Milagre C, Pearce OM, Reynolds LE, Hodivala-Dilke K, Leinster DA, et al. Interleukin-6 stimulates defective angiogenesis. Cancer Res. 2015;75:3098–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mondal A, Smith C, DuHadaway JB, Sutanto-Ward E, Prendergast GC, Bravo-Nuevo A, et al. IDO1 is an integral mediator of inflammatory neovascularization. EBioMedicine. 2016;14:74–82.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Palmer GM, Tiran Z, Zhou Z, Capozzi ME, Park W, Coletta C, et al. A novel angiopoietin-derived peptide displays anti-angiogenic activity and inhibits tumour-induced and retinal neovascularization. Br J Pharmacol. 2012;165:1891–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Stahl A, Joyal JS, Chen J, Sapieha P, Juan AM, Hatton CJ, et al. SOCS3 is an endogenous inhibitor of pathologic angiogenesis. Blood. 2012;120:2925–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Prendergast GC, Metz R, Muller AJ, Merlo LM, Mandik-Nayak L. IDO2 in immunomodulation and autoimmune disease. Front Immunol. 2014;5:585.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Yuasa HJ, Takubo M, Takahashi A, Hasegawa T, Noma H, Suzuki T. Evolution of vertebrate indoleamine 2,3-dioxygenases. J Mol Evol. 2007;65:705–14.

    Article  CAS  PubMed  Google Scholar 

  54. Metz R, Smith C, DuHadaway JB, Chandler P, Baban B, Merlo LM, et al. IDO2 is critical for IDO1-mediated T cell regulation and exerts a non-redundant function in inflammation. Int Immunol. 2014;26:357–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Eldredge HB, Denittis A, DuHadaway JB, Chernick M, Metz R, Prendergast GC. Concurrent whole brain radiotherapy and short-course chloroquine in patients with brain metastases: a pilot trial. J Radiat Oncol. 2013;2:315–21.

    Article  CAS  Google Scholar 

  56. Li J, Li Y, Yang D, Hu N, Guo Z, Kuang C, et al. Establishment of a human indoleamine 2, 3-dioxygenase 2 (hIDO2) bioassay system and discovery of tryptanthrin derivatives as potent hIDO2 inhibitors. Eur J Med Chem. 2016;123:171–9.

    Article  CAS  PubMed  Google Scholar 

  57. Trabanelli S, Ocadlikova D, Ciciarello M, Salvestrini V, Lecciso M, Jandus C, et al. The SOCS3-independent expression of IDO2 supports the homeostatic generation of T regulatory cells by human dendritic cells. J Immunol. 2014;192:1231–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Merlo LM, Pigott E, DuHadaway JB, Grabler S, Metz R, Prendergast GC, et al. IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. J Immunol. 2014;92:2082–90.

    Article  CAS  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. van Baren N, Van den Eynde BJ. Tryptophan-degrading enzymes in tumoral immune resistance. Front Immunol. 2015;6:34.

    PubMed  PubMed Central  Google Scholar 

  61. Merlo LM, DuHadaway JB, Grabler S, Prendergast GC, Muller AJ, Mandik-Nayak L. IDO2 modulates T cell-dependent autoimmune responses through a B cell-intrinsic mechanism. J Immunol. 2016;196:4487–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Merlo LM, Grabler S, DuHadaway JB, Pigott E, Manley K, Prendergast GC, et al. Therapeutic antibody targeting of indoleamine-2,3-dioxygenase (IDO2) inhibits autoimmune arthritis. Clin Immunol. 2017;179:8–16.

    Article  CAS  PubMed  Google Scholar 

  63. Affara NI, Ruffell B, Medler TR, Gunderson AJ, Johansson M, Bornstein S, et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell. 2014;25:809–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H, Nedospasov S, et al. B regulatory cells and the tumor-promoting actions of TNF-alpha during squamous carcinogenesis. Proc Natl Acad Sci U S A. 2011;108:10662–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Röhrig UF, Majjigapu SR, Caldelari D, Dilek N, Reichenbach P, Ascencao K, et al. 1,2,3-Triazoles as inhibitors of indoleamine 2,3-dioxygenase 2 (IDO2). Bioorg Med Chem Lett. 2016;26:4330–3.

    Article  PubMed  CAS  Google Scholar 

  66. Austin CJ, Mailu BM, Maghzal GJ, Sanchez-Perez A, Rahlfs S, Zocher K, et al. Biochemical characteristics and inhibitor selectivity of mouse indoleamine 2,3-dioxygenase-2. Amino Acids. 2010;39:565–78.

    Article  CAS  PubMed  Google Scholar 

  67. Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ. Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2. Bioorg Med Chem Lett. 2012;22:7641–6.

    Article  CAS  PubMed  Google Scholar 

  68. Pantouris G, Serys M, Yuasa HJ, Ball HJ, Mowat CG. Human indoleamine 2,3-dioxygenase-2 has substrate specificity and inhibition characteristics distinct from those of indoleamine 2,3-dioxygenase-1. Amino Acids. 2014;46:2155–63.

    Article  CAS  PubMed  Google Scholar 

  69. Witkiewicz AK, Costantino CL, Metz R, Muller AJ, Prendergast GC, Yeo CJ, et al. Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J Am Coll Surg. 2009;208:781–7. discussion 7-9

    Article  PubMed  PubMed Central  Google Scholar 

  70. Prendergast GC. A perspective on cancer as an abortive autoimmune response to altered-self. Cancer Res. 2015;75:3–4.

    Article  CAS  PubMed  Google Scholar 

  71. Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012;72:5435–40.

    Article  CAS  PubMed  Google Scholar 

  72. Platten M, von Knebel DN, Oezen I, Wick W, Ochs K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front Immunol. 2014;5:673.

    PubMed  Google Scholar 

  73. van Baren N, Van den Eynde BJ. Tumoral immune resistance mediated by enzymes that degrade tryptophan. Cancer Immunol Res. 2015;3:978–85.

    Article  PubMed  CAS  Google Scholar 

  74. Salter M, Hazelwood R, Pogson CI, Iyer R, Madge DJ. The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat. Biochem Pharmacol. 1995;49:1435–42.

    Article  CAS  PubMed  Google Scholar 

  75. Dolusic E, Larrieu P, Moineaux L, Stroobant V, Pilotte L, Colau D, et al. Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators. J Med Chem. 2011;54:5320–34.

    Article  CAS  PubMed  Google Scholar 

  76. Pilotte L, Larrieu P, Stroobant V, Colau D, Dolusic E, Frederick R, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pantouris G, Mowat CG. Antitumour agents as inhibitors of tryptophan 2,3-dioxygenase. Biochem Biophys Res Commun. 2014;443:28–31.

    Article  CAS  PubMed  Google Scholar 

  78. Wu JS, Lin SY, Liao FY, Hsiao WC, Lee LC, Peng YH, et al. Identification of substituted naphthotriazolediones as novel tryptophan 2,3-dioxygenase (TDO) inhibitors through structure-based virtual screening. J Med Chem. 2015;58:7807–19.

    Article  CAS  PubMed  Google Scholar 

  79. Abdel-Magid AF. Targeting the inhibition of tryptophan 2,3-dioxygenase (TDO-2) for cancer treatment. ACS Med Chem Lett. 2017;8:11–3.

    Article  CAS  PubMed  Google Scholar 

  80. Kanai M, Funakoshi H, Takahashi H, Hayakawa T, Mizuno S, Matsumoto K, et al. Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Mol Brain. 2009;2:8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, et al. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature. 2014;511:184–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Larkin PB, Sathyasaikumar KV, Notarangelo FM, Funakoshi H, Nakamura T, Schwarcz R, et al. Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice. Biochim Biophys Acta. 2016;1860:2345–54.

    Article  CAS  PubMed  Google Scholar 

  83. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478:197–203.

    Article  CAS  PubMed  Google Scholar 

  84. D’Amato NC, Rogers TJ, Gordon MA, Greene LI, Cochrane DR, Spoelstra NS, et al. A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res. 2015;75:4651–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop LD, Metz R, et al. IDO in inflammatory programming and immune suppression in cancer. In: Gabrilovich DI, Hurwitz AA, editors. Tumor-induced immune suppression. New York: Springer; 2014.

    Google Scholar 

  86. Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother. 2014;63:721–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Soliman HH, Minton SE, Han HS, Ismail-Khan R, Neuger A, Khambati F, et al. A phase I study of indoximod in patients with advanced malignancies. Oncotarget. 2016;7:22928–38.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Soliman HH, Jackson E, Neuger T, Dees EC, Harvey RD, Han H, et al. A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors. Oncotarget. 2014;5:8136–46.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Prendergast GC, Metz R. A perspective on new immune adjuvant principles: Reprogramming inflammatory states to permit clearance of cancer cells and other age-associated cellular pathologies. Oncoimmunology. 2012;1:924–9.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Cady SG, Sono M. 1-methyl-DL-tryptophan, beta-(3-benzofuranyl)-DL-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b)thienyl]-DL-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch Biochem Biophys. 1991;291:326–33.

    Article  CAS  PubMed  Google Scholar 

  91. Peterson AC, Migawa MT, Martin MJ, Hamaker LK, Czerwinski KM, Zhang W, et al. Evaluation of functionalized tryptophan derivatives and related compounds as competitive inhibitors of indoleamine 2,3-dioxygenase. Med Chem Res. 1994;3:531–44.

    CAS  Google Scholar 

  92. Sono M, Cady SG. Enzyme kinetic and spectroscopic studies of inhibitor and effector interactions with indoleamine 2,3-dioxygenase. 1. Norharman and 4-phenylimidazole binding to the enzyme as inhibitors and heme ligands. Biochemistry. 1989;28:5392–9.

    Article  CAS  PubMed  Google Scholar 

  93. Sugimoto H, Oda S, Otsuki T, Hino T, Yoshida T, Shiro Y. Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc Natl Acad Sci U S A. 2006;103:2611–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gaspari P, Banerjee T, Malachowski WP, Muller AJ, Prendergast GC, DuHadaway J, et al. Structure-activity study of brassinin derivatives as indoleamine 2,3-dioxygenase inhibitors. J Med Chem. 2006;49:684–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rohrig UF, Majjigapu SR, Grosdidier A, Bron S, Stroobant V, Pilotte L, et al. Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition. J Med Chem. 2012;55:5270–90.

    Article  CAS  PubMed  Google Scholar 

  96. Mautino MR, Jaipuri FA, Waldo J, Kumar S, Adams J, Van Allen C, et al. NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. Cancer Res. 2013;73(8 Suppl):491.

    Article  Google Scholar 

  97. Spahn J, Peng J, Lorenzana E, Kan D, Hunsaker T, Segal E, et al. Improved anti-tumor immunity and efficacy upon combination of the IDO1 inhibitor GDC-0919 with anti-PD-L1 blockade versus anti-PD-L1 alone in preclinical tumor models. J Immunother Cancer. 2015;3(Suppl 2):303.

    Article  Google Scholar 

  98. Nayak A, Hao Z, Sadek R, Dobbins R, Marshall L, Vahanian NN, et al. Phase 1a study of the safety, pharmacokinetics, and pharmacodynamics of GDC-0919 in patients with recurrent/advanced solid tumors. In: European Cancer Conference, Vienna, Austria, 2015.

    Google Scholar 

  99. Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B, et al. INCB24360 (epacadostat), a highly potent and selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor for immuno-oncology. ACS Med Chem Lett. 2017;8:486–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood. 2010;115:3520–30.

    Article  CAS  PubMed  Google Scholar 

  101. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Beatty GL, O'Dwyer PJ, Clark J, Shi JG, Bowman KJ, Scherle P, et al. First-in-human phase 1 study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res 2017

    Google Scholar 

  103. Gibney GT, Hamid O, Lutzky J, Olszanski AJ, Gangadhar TC, Gajewski TF, et al. Updated results from a Phase 1/2 study of epacadostat (INCB024360) in combination with ipilimumab in patients with metastatic melanoma. Eur J Cancer. 2015;51:S106–7.

    Article  Google Scholar 

  104. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gangadhar TC, Hamid O, Smith DC, Bauer TM, Wasser JS, Olszanski AJ, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: updated Phase 1 results from ECHO-202/KEYNOTE-037. Ann Oncol. 2016;27:379–400.

    Article  Google Scholar 

  106. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521–32.

    Article  CAS  PubMed  Google Scholar 

  107. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17.

    Article  PubMed  Google Scholar 

  108. Metz R, Rust S, DuHadaway JB, Mautino MR, Munn DH, Vahanian NN, et al. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Vogel CF, Goth SR, Dong B, Pessah IN, Matsumura F. Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem Biophys Res Commun. 2008;375:331–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A. 2010;107:19961–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Major research grants support to G.C.P., W.J.M., and A.J.M. is acknowledged from the NIH, the US Department of Defense Breast and Lung Cancer Research Programs, Susan G. Komen for the Cure and The W.W. Smith Trust, with additional support provided by NewLink Genetics Corporation, Sharpe-Strumia Research Foundation, Dan Green Foundation, Lankenau Medical Center Foundation, and the Main Line Health System.

Conflict of Interest

G.C.P., W.J.M., and A.J.M. state a conflict of interest as inventors, shareholders, grant recipients, and advisors with NewLink Genetics Corporation, licensee of IDO-related intellectual property from the Lankenau Institute of Medical Research as described in US Patents 7705022, 7714139, 8008281, 8058416, 8383613, 8389568, 8436151, 8476454, and 8586636. The other authors state no conflict of interest. P.A.S. is an employee and shareholder of Incyte Corporation.

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Authors and Affiliations

  1. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    George C. Prendergast & Alexander J. Muller

  2. Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA, 19096, USA

    George C. Prendergast, Arpita Mondal & Alexander J. Muller

  3. Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, USA

    William J. Malachowski

  4. Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA

    Arpita Mondal

  5. Incyte Corporation Inc., Wilmington, DE, USA

    Peggy Scherle

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  1. George C. Prendergast
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Correspondence to George C. Prendergast .

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  1. Gustave Roussy Cancer Center , Villejuif Cedex, France

    Laurence Zitvogel

  2. Gustave Roussy Cancer Center , Villejuif Cedex, France

    Guido Kroemer

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Prendergast, G.C., Malachowski, W.J., Mondal, A., Scherle, P., Muller, A.J. (2018). IDO/TDO Inhibition in Cancer. In: Zitvogel, L., Kroemer, G. (eds) Oncoimmunology. Springer, Cham. https://doi.org/10.1007/978-3-319-62431-0_17

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