Review Article | Published:

Immune control by amino acid catabolism during tumorigenesis and therapy

Nature Reviews Cancer (2019) | Download Citation


Immune checkpoints arise from physiological changes during tumorigenesis that reprogramme inflammatory, immunological and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunological tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) is a common TME hallmark at clinical presentation of cancer. Cells catabolizing Trp and Arg suppress effector T cells and stabilize regulatory T cells to suppress immunity in chronic inflammatory diseases of clinical importance, including cancers. Processes that induce Trp and Arg catabolism in the TME remain incompletely defined. Indoleamine 2,3 dioxygenase (IDO) and arginase 1 (ARG1), which catabolize Trp and Arg, respectively, respond to inflammatory cues including interferons and transforming growth factor-β (TGFβ) cytokines. Dying cells generate inflammatory signals including DNA, which is sensed to stimulate the production of type I interferons via the stimulator of interferon genes (STING) adaptor. Thus, dying cells help establish local conditions that suppress antitumour immunity to promote tumorigenesis. Here, we review evidence that Trp and Arg catabolism contributes to inflammatory processes that promote tumorigenesis, impede immune responses to therapy and might promote neurological comorbidities associated with cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Database:

Kaplan–Meier Plotter:

The Human Protein Atlas:


  1. 1.

    Bissell, M. J. & Hines, W. C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320–329 (2011).

  2. 2.

    Vesely, M. D. & Schreiber, R. D. Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. Ann. NY Acad. Sci. 1284, 1–5 (2013).

  3. 3.

    Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

  4. 4.

    Casero, R. A. Jr, Murray Stewart, T. & Pegg, A. E. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat. Rev. Cancer 18, 681–695 (2018).

  5. 5.

    Garber, K. A new cancer immunotherapy suffers a setback. Science 360, 588 (2018).

  6. 6.

    Mitchell, T. C. et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J. Clin Oncol. 36, 3223–3230 (2018).

  7. 7.

    Muller, A. J., Manfredi, M., Zakharia, Y. & Prendergast, G. C. IDO inhibitors for cancer treatment: lessons from ECHO-301. Semin. Immunopathol. 41, 41–48 (2019).

  8. 8.

    Seymour, R. L., Ganapathy, V., Mellor, A. L. & Munn, D. H. A high-affinity, tryptophan-selective amino acid transport system in human macrophages. J. Leukoc. Biol. 80, 1320–1327 (2006).

  9. 9.

    Ron, D. Translational control in the endoplasmic reticulum stress response. J. Clin. Invest. 110, 1383–1388 (2002).

  10. 10.

    Lehman, S. L., Ryeom, S. & Koumenis, C. Signaling through alternative Integrated Stress Response pathways compensates for GCN2 loss in a mouse model of soft tissue sarcoma. Sci. Rep. 5, 11781 (2015).

  11. 11.

    Mossmann, D., Park, S. & Hall, M. N. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat. Rev. Cancer 18, 744–757 (2018).

  12. 12.

    Cormerais, Y. et al. Genetic disruption of the multifunctional CD98/LAT1 complex demonstrates the key role of essential amino acid transport in the control of mTORC1 and tumor growth. Cancer Res. 76, 4481–4492 (2016).

  13. 13.

    Esaki, N. et al. ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer. Cancer Sci. 109, 141–153 (2018).

  14. 14.

    Wyant, G. A. et al. mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient. Cell 171, 642–654 (2017).

  15. 15.

    Muller, A. J. et al. Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc. Natl Acad. Sci. USA 105, 17073–17078 (2008). This genetic study of IDO establishes its key contributions to formation of a pathogenic inflammatory milieu that is critical for malignant development.

  16. 16.

    Smith, C. et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov. 2, 722–735 (2012). This study offers genetic evidence that IDO is crucial for tumour formation, vasculogenesis, metastasis and MDSC activation and recruitment.

  17. 17.

    Metz, R. et al. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology 1, 1460–1468 (2012).

  18. 18.

    Mautino, M. R. et al. A novel prodrug of indoximod with enhanced pharmacokinetic properties. Cancer Res. 77 (Suppl. 13), 4076 (2017).

  19. 19.

    Friberg, M. et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int. J. Cancer 101, 151–155 (2002).

  20. 20.

    Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E. & Prendergast, G. C. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med. 11, 312–319 (2005). This study links IDO to a cancer pathway and shows that IDO inhibitors can exert robust antitumour effects if combined with DNA-damaging chemotherapy.

  21. 21.

    Hou, D. Y. et al. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. 67, 792–801 (2007).

  22. 22.

    Lemos, H. et al. STING promotes the growth of tumors characterized by low antigenicity via IDO activation. Cancer Res. 76, 2076–2081 (2016). This study shows that STING promotes growth of poorly immunogenic tumours by stimulating DCs in TDLNs to express IDO.

  23. 23.

    Weiner, G. J. CpG oligodeoxynucleotide-based therapy of lymphoid malignancies. Adv. Drug Deliv. Rev. 61, 263–267 (2009).

  24. 24.

    Unterholzner, L. The interferon response to intracellular DNA: why so many receptors? Immunobiology 218, 1312–1321 (2013).

  25. 25.

    Prendergast, G. C., Metz, R., Muller, A. J., Merlo, L. M. & Mandik-Nayak, L. IDO2 in immunomodulation and autoimmune disease. Front. Immunol. 5, 585 (2014).

  26. 26.

    Badawy, A. A. Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements. Neuropharmacology 112, 248–263 (2017).

  27. 27.

    Morris, G., Carvalho, A. F., Anderson, G., Galecki, P. & Maes, M. The many neuroprogressive actions of tryptophan catabolites (TRYCATs) that may be associated with the pathophysiology of neuro-immune disorders. Curr. Pharm. Des. 22, 963–977 (2016).

  28. 28.

    Thomas, S. R., Mohr, D. & Stocker, R. Nitric oxide inhibits indoleamine 2,3-dioxygenase activity in interferon-gamma primed mononuclear phagocytes. J. Biol. Chem. 269, 14457–14464 (1994).

  29. 29.

    Hesterberg, R. S., Cleveland, J. L. & Epling-Burnette, P. K. Role of polyamines in immune cell functions. Med. Sci. 6, E22 (2018).

  30. 30.

    Boutard, V. et al. Transforming growth factor-beta stimulates arginase activity in macrophages. Implications for the regulation of macrophage cytotoxicity. J. Immunol. 155, 2077–2084 (1995).

  31. 31.

    Pallotta, M. T. et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat. Immunol. 12, 870–878 (2011).

  32. 32.

    Theate, I. et al. Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol. Res. 3, 161–172 (2015).

  33. 33.

    Munn, D. H. & Mellor, A. L. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 37, 193–207 (2016).

  34. 34.

    El-Zaatari, M. et al. Indoleamine 2,3-dioxygenase 1, increased in human gastric pre-neoplasia, promotes inflammation and metaplasia in mice and is associated with type II hypersensitivity/autoimmunity. Gastroenterology 154, 140–153 (2018).

  35. 35.

    Platten, M., Wick, W. & Van den Eynde, B. J. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 72, 5435–5440 (2012).

  36. 36.

    Prendergast, G. C., Malachowski, W. P., DuHadaway, J. B. & Muller, A. J. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 77, 6795–6811 (2017).

  37. 37.

    Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 9, 1269–1274 (2003). This is an early report highlighting that elevated IDO expression is a common TME feature and that IDO inhibition can enhance T cell accumulation in the TME.

  38. 38.

    Witkiewicz, A. K. et al. Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J. Am. Coll. Surg. 208, 781–787; discussion 787–789 (2009).

  39. 39.

    Brandacher, G. et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin. Cancer Res. 12, 1144–1151 (2006). This is one of the earliest studies to establish that high IDO activity in human tumours tends to associate with a poor prognosis.

  40. 40.

    Yu, J. et al. Upregulated expression of indoleamine 2,3-dioxygenase in primary breast cancer correlates with increase of infiltrated regulatory T cells in situ and lymph node metastasis. Clin. Dev. Immunol. 2011, 1–10 (2011).

  41. 41.

    Qian, F. et al. Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T cell proliferation in human epithelial ovarian cancer. Cancer Res. 69, 5498–5504 (2009).

  42. 42.

    Feder-Mengus, C. et al. High expression of indoleamine 2,3-dioxygenase gene in prostate cancer. Eur. J. Cancer 44, 2266–2275 (2008).

  43. 43.

    Brody, J. R. et al. Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle 8, 1930–1934 |(2009).

  44. 44.

    Corm, S. et al. Indoleamine 2,3-dioxygenase activity of acute myeloid leukemia cells can be measured from patients’ sera by HPLC and is inducible by IFN-gamma. Leuk. Res. 33, 490–494 (2009).

  45. 45.

    Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011). This study links TDO activity with AHR signalling and shows that this pathway promotes tumour development.

  46. 46.

    D’Amato, N. C. et al. A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res. 75, 4651–4664 (2015).

  47. 47.

    Wei, L. et al. High indoleamine 2,3-dioxygenase is correlated with microvessel density and worse prognosis in breast cancer. Front. Immunol. 9, 724 (2018).

  48. 48.

    Sinclair, L. V. et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14, 500–508 (2013). This study reveals an obligatory requirement for activated T cells to upregulate amino acid transporter activity to stimulate mTOR and differentiate into effector T cells.

  49. 49.

    Lee, G. K. et al. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107, 1–9 (2002).

  50. 50.

    Munn, D. H. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 1–10 (2005). This study identifies a critical requirement for GCN2 signalling for T cells to proliferate and differentiate.

  51. 51.

    Rodriguez, P. C., Quiceno, D. G. & Ochoa, A. C. L-Arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568–1573 (2007). This study links Arg catabolism to blocking T cell entry into cell cycle via a GCN2-dependent mechanism.

  52. 52.

    Sharma, M. D. et al. The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci. Adv. 1, e1500845 (2015).

  53. 53.

    Sharma, M. D. et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33, 942–954 (2010).

  54. 54.

    Sharma, M. D. et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via IDO. J. Clin. Invest. 117, 2570–2582 (2007).

  55. 55.

    Sharma, M. D. et al. An inherently bi-functional subset of Foxp3 + Treg/T-helper cells is controlled by the transcription factor Eos. Immunity 38, 998–1012 (2013).

  56. 56.

    Munn, D. H. et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. Invest. 114, 280–290 (2004). This study identifies IDO-expressing DCs in TDLNs as potent regulators of T cell immunity.

  57. 57.

    Munn, D. H. et al. Potential regulatory function of human dendritic cells expressing IDO. Science 297, 1867–1870 (2002).

  58. 58.

    Chen, W., Liang, X., Peterson, A. J., Munn, D. H. & Blazar, B. R. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J. Immunol. 181, 5396–5404 (2008).

  59. 59.

    Lee, J. R. et al. Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma. Lab. Invest. 83, 1457–1466 (2003).

  60. 60.

    Montero, A. J., Diaz-Montero, C. M., Kyriakopoulos, C. E., Bronte, V. & Mandruzzato, S. Myeloid-derived suppressor cells in cancer patients: a clinical perspective. J. Immunother. 35, 107–115 (2012).

  61. 61.

    Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nat. Rev. Immunol. 5, 641–654 (2005).

  62. 62.

    Holmgaard, R. B. et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. 13, 412–424 (2015). This report shows that IDO inhibitors can phenocopy IDO genetic blockade in blunting MDSC recruitment and activation in the TME.

  63. 63.

    Gielen, P. R. et al. Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function. Neuro Oncol. 18, 1253–1264 (2016).

  64. 64.

    Zhang, H. et al. Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer. Blood 122, 1105–1113 (2013).

  65. 65.

    Mellor, A. L. et al. Cutting edge: CpG oligonucleotides induce splenic CD19+dendritic cells to acquire potent IDO-dependent T cell regulatory functions via IFN type 1 signaling. J. Immunol. 175, 5601–5605 (2005).

  66. 66.

    Ravishankar, B. et al. Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc. Natl Acad. Sci. USA 109, 3909–3914 (2012).

  67. 67.

    Ravishankar, B. et al. The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity. Proc. Natl Acad. Sci. USA 112, 10774–10779 (2015).

  68. 68.

    Ravishankar, B. et al. Marginal zone CD169+macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proc. Natl Acad. Sci. USA 111, 4215–4220 (2014).

  69. 69.

    Huang, L. et al. Cutting edge: DNA sensing via the STING adaptor in myeloid dendritic cells induces potent tolerogenic responses. J. Immunol. 191, 3509–3513 (2013).

  70. 70.

    Huang, L. et al. Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells. J. Immunol. 188, 4913–4920 (2012).

  71. 71.

    Munn, D. H., Sharma, M. D. & Mellor, A. L. Ligation of B7-1/B7-2 by human CD4(+) T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J. Immunol. 172, 4100–4110 (2004).

  72. 72.

    Baban, B. et al. Physiologic control of IDO competence in splenic dendritic cells. J. Immunol. 187, 2329–2335 (2011).

  73. 73.

    Xia, T., Konno, H., Ahn, J. & Barber, G. N. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep. 14, 282–297 (2016). This study identifies correlations between reduced STING signalling in human colorectal carcinoma, reduced responses to DNA damage and tumorigenesis.

  74. 74.

    Ahn, J., Xia, T., Rabasa Capote, A., Betancourt, D. & Barber, G. N. Extrinsic phagocyte-dependent STING signaling dictates the immunogenicity of dying cells. Cancer Cell 33, 862–873 (2018).

  75. 75.

    Shinde, R. et al. Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. Nat. Immunol. 19, 571–582 (2018).

  76. 76.

    Romani, L. & Puccetti, P. Protective tolerance to fungi: the role of IL-10 and tryptophan catabolism. Trends Microbiol. 14, 183–189 (2006).

  77. 77.

    DiNatale, B. C. et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol. Sci. 115, 89–97 (2010).

  78. 78.

    Duarte, J. H., Di Meglio, P., Hirota, K., Ahlfors, H. & Stockinger, B. Differential influences of the aryl hydrocarbon receptor on Th17 mediated responses in vitro and in vivo. PLOS ONE 8, e79819 (2013).

  79. 79.

    Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).

  80. 80.

    Nguyen, N. T. et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc. Natl Acad. Sci. USA 107, 19961–19966 (2010).

  81. 81.

    Vogel, C. F., Goth, S. R., Dong, B., Pessah, I. N. & Matsumura, F. Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem. Biophys. Res. Commun. 375, 331–335 (2008).

  82. 82.

    Litzenburger, U. M. et al. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget 5, 1038–1051 (2014).

  83. 83.

    Feng, S., Cao, Z. & Wang, X. Role of aryl hydrocarbon receptor in cancer. Biochim. Biophys. Acta 1836, 197–210 (2013).

  84. 84.

    Lewis, H. C., Chinnadurai, R., Bosinger, S. E. & Galipeau, J. The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells. Oncotarget 8, 91914–91927 (2017).

  85. 85.

    Ehrlich, A. K. & Kerkvliet, N. I. Is chronic AhR activation by rapidly metabolized ligands safe for the treatment of immune-mediated diseases? Curr. Opin. Toxicol. 2, 72–78 (2017).

  86. 86.

    Hayashi, T. et al. 3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis. Proc. Natl Acad. Sci. USA 104, 18619–18624 (2007).

  87. 87.

    Yan, Y. et al. IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J. Immunol. 185, 5953–5961 (2010).

  88. 88.

    Cronin, S. J. F. et al. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 563, 564–568 (2018).

  89. 89.

    Adams, S. et al. Involvement of the kynurenine pathway in human glioma pathophysiology. PLOS ONE 9, e112945 (2014).

  90. 90.

    Sahm, F. et al. The endogenous tryptophan metabolite and NAD+precursor quinolinic acid confers resistance of gliomas to oxidative stress. Cancer Res. 73, 3225–3234 (2013).

  91. 91.

    Triplett, T. A. et al. Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nat. Biotechnol. 36, 758–764 (2018).

  92. 92.

    Sculier, J. P. et al. Medical anticancer treatment of lung cancer associated with comorbidities: a review. Lung Cancer 87, 241–248 (2015).

  93. 93.

    Capuron, L. & Dantzer, R. Cytokines and depression: the need for a new paradigm. Brain Behav. Immun. 17, S119–S124 (2003).

  94. 94.

    Sui, H. et al. 5-Hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/beta-catenin/MMP-7 signaling pathway. Oncotarget 6, 25975–25987 (2015).

  95. 95.

    Gwynne, W. D. et al. Serotonergic system antagonists target breast tumor initiating cells and synergize with chemotherapy to shrink human breast tumor xenografts. Oncotarget 8, 32101–32116 (2017).

  96. 96.

    Kim, H. et al. Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J. Clin. Invest. 122, 2940–2954 (2012).

  97. 97.

    Huang, L. et al. Virus infections incite pain hypersensitivity by inducing indoleamine 2,3 dioxygenase. PLOS Pathog. 12, e1005615 (2016).

  98. 98.

    LaVoy, E. C., Fagundes, C. P. & Dantzer, R. Exercise, inflammation, and fatigue in cancer survivors. Exerc. Immunol. Rev. 22, 82–93 (2016).

  99. 99.

    Beatty, G. L. et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin. Cancer Res. 23, 3269–3276 (2017).

  100. 100.

    Cheong, J. E., Ekkati, A. & Sun, L. A patent review of IDO1 inhibitors for cancer. Expert Opin. Ther. Pat. 28, 317–330 (2018).

  101. 101.

    Fuertes, M. B. et al. Host type I IFN signals are required for antitumor CD8+T cell responses through CD8{alpha}+dendritic cells. J. Exp. Med. 208, 2005–2016 (2011). This study shows that type I interferon signals mediated by DCs in the TME promote effector T cell responses.

  102. 102.

    Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).

  103. 103.

    Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).

  104. 104.

    Corrales, L. et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030 (2015). References 102–104 show that STING–type I interferon signalling incites immunity directed at immunogenic tumours and that synthetic STING agonists amplify this antitumour response.

  105. 105.

    Li, T. et al. Antitumor activity of cGAMP via stimulation of cGAS-cGAMP-STING-IRF3 mediated innate immune response. Sci. Rep. 6, 19049 (2016).

  106. 106.

    Lemos, H. et al. Activation of the STING adaptor attenuates experimental autoimmune encephalitis. J. Immunol. 192, 5571–5578 (2014).

  107. 107.

    Aya, F. et al. Life-threatening colitis and complete response with ipilimumab in a patient with metastatic BRAF-mutant melanoma and rheumatoid arthritis. ESMO Open 1, e000032 (2016).

  108. 108.

    De Martin, E. et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J. Hepatol. 68, 1181–1190 (2018).

  109. 109.

    Menzies, A. M. et al. Anti-PD1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann. Oncol. 28, 368–376 (2017).

  110. 110.

    Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2016).

  111. 111.

    Banerjee, T. et al. A key in vivo antitumor mechanism of action of natural product-based brassinins is inhibition of indoleamine 2,3-dioxygenase. Oncogene 27, 2851–2857 (2008).

  112. 112.

    Ursu, R. et al. Intracerebral injection of CpG oligonucleotide for patients with de novo glioblastoma-A phase II multicentric, randomised study. Eur. J. Cancer 73, 30–37 (2017).

  113. 113.

    Moreno Ayala, M. A. et al. Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer. J. Cancer Res. Clin. Oncol. 143, 1713–1732 (2017).

  114. 114.

    Tarhini, A. A., Gogas, H. & Kirkwood, J. M. IFN-alpha in the treatment of melanoma. J. Immunol. 189, 3789–3793 (2012).

  115. 115.

    Mojic, M., Takeda, K. & Hayakawa, Y. The dark side of IFN-gamma: its role in promoting cancer immunoevasion. Int. J. Mol. Sci. 19, 89 (2017).

  116. 116.

    McMasters, K. M. et al. Final results of the Sunbelt melanoma trial: a multi-institutional prospective randomized phase III study evaluating the role of adjuvant high-dose interferon alfa-2b and completion lymph node dissection for patients staged by sentinel lymph node biopsy. J. Clin. Oncol. 34, 1079–1086 (2016).

  117. 117.

    Mautino, M. R. et al. NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. Cancer Res. 73 (Suppl. 8), 491 (2013).

  118. 118.

    Nayak-Kapoor, A. et al. Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J. Immunother.Cancer. 6, 61 (2018).

  119. 119.

    Siu, L. L. et al. BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo) in advanced cancers in a phase 1/2a trial. Cancer Res. 77 (Suppl. 13), CT116 (2017).

  120. 120.

    Reardon, D. et al. ATIM-29. A phase 1 study of PF-06840003, an oral indole 2,3-dioxygenase 1 (IDO1) inhibitor in patients with malignant gliomas. Neuro Oncol. 19, vi32 (2017).

  121. 121.

    Sahebjam, S. et al. KHK2455, a long-acting selective IDO-1 inhibitor, in combination with mogamulizumab, an anti-CCR4 monoclonal antibody, in patients with advanced solid tumors: preliminary safety report and pharmacodynamic activity from a first-in-human study [abstract P148]. Presented at the 2017 Society for Immunotherapy of Cancer (SITC) Annual Meeting (2017).

  122. 122.

    Mautino, M. et al. A novel prodrug of indoximod with enhanced pharmacokinetic properties. Cancer Res. 77, 4076 (2017).

  123. 123.

    Herbst, R. S. et al. Predictive correlates of response to the anti-PDL1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

  124. 124.

    Spranger, S. et al. Up-regulation of PDL1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci. Transl Med. 5, 200ra116 (2013).

  125. 125.

    Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D. & Allison, J. P. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210, 1389–1402 (2013). This study suggests that IDO blockade can empower immune checkpoint therapy.

  126. 126.

    Spranger, S. et al. Mechanism of tumor rejection with doublets of CTLA-4, PD1/PDL1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J. Immunother. Cancer 2, 3 (2014).

  127. 127.

    Wainwright, D. A. et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PDL1 in mice with brain tumors. Clin. Cancer Res. 20, 5290–5301 (2014).

  128. 128.

    Zakharia, Y. et al. Interim analysis of the phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma. Cancer Res. 77 (Suppl. 13), CT117 (2017).

  129. 129.

    Zakharia, Y. et al. Updates on phase1b/2 trial of the indoleamine 2,3-dioxygenase pathway inhibitor indoximod plus checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma. J. Clin. Oncol. 34 (Suppl.), 3075 (2016).

  130. 130.

    Zakharia, Y., Munn, D., Link, C., Vahanian, N. & Kennedy, E. ACTR-53. Interim analysis of Phase 1b/2 combination of the IDO pathway inhibitor indoximod with temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors. Neuro Oncol. 18, vi13–vi14 (2016).

  131. 131.

    Smith, D. C. et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: preliminary phase I/II results of ECHO-202/KEYNOTE-037. J. Clin. Oncol. 35 (Suppl.), 4503 (2017).

  132. 132.

    Lara, P. et al. Epacadostat plus pembrolizumab in patients with advanced RCC: preliminary phase I/II results from ECHO-202/KEYNOTE-037. J. Clin. Oncol. 35 (Suppl.), 4515 (2017).

  133. 133.

    Gangadhar, T. C. et al. Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: preliminary phase I/II results of ECHO-202/KEYNOTE-037. J. Clin. Oncol. 35, 9014 (2017).

  134. 134.

    Hamid, O. et al. Epacadostat plus pembrolizumab in patients with SCCHN: preliminary phase I/II results from ECHO-202/KEYNOTE-037. J. Clin. Oncol. 35 (Suppl.), 6010 (2017).

  135. 135.

    US National Library of Medicine. (2018).

  136. 136.

    Long, G. V. et al. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: Results of the phase 3 ECHO-301/KEYNOTE-252 study. J. Clin. Oncol. 36 (Suppl.), 108 (2018).

  137. 137.

    Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 (2015).

  138. 138.

    Li, M. et al. The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J. Immunother. Cancer 2, 21 (2014).

  139. 139.

    Johnson, T. S. & Munn, D. H. Host indoleamine 2,3-dioxygenase: contribution to systemic acquired tumor tolerance. Immunol. Invest. 41, 765–797 (2012).

  140. 140.

    Soliman, H. 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 5, 8136–8146 (2014).

  141. 141.

    Bahary, N. et al. Phase 2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: interim analysis. J. Clin. Oncol. 34 (Suppl.), 3020 (2016).

  142. 142.

    Bahary, N. et al. Results of the phase Ib portion of a phase I/II trial of the indoleamine 2, 3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreatic cancer. J. Clin. Oncol. 34 (Suppl.), 452 (2016).

  143. 143.

    Emadi, A. et al. Indoximod in combination with idarubicin and cytarabine for upfront treatment of patients with newly diagnosed acute myeloid leukemia (AML): phase 1 report [abstract E912]. Presented at the 22nd European Hematologic Association (EHA) Congress (2017).

  144. 144.

    Johnson, T. S. et al. PDCT-06. Radio-immunotherapy using the IDO-inhibitor indoximod in combination with re-irradiation for children with progressive brain tumors in the phase 1 setting: an updated report of safety and tolerability (NCT02502708). Neuro Oncol. 19, vi185 (2017).

  145. 145.

    Johnson, T. S. et al. Safety and tolerability of combining the IDO-inhibitor indoximod with re-irradiation for pediatric patients with progressive brain tumors treated on the NLG-2105 phase 1 trial (NCT02502708) [abstract 4027]. Presented at the 2017 American Society of Pediatric Hematology Oncology (ASPHO) Annual Meeting (2017).

  146. 146.

    Lugade, A. A. et al. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J. Immunol. 180, 3132–3139 (2008).

  147. 147.

    Ladomersky, E. et al. IDO1 inhibition synergizes with radiation and PD1 blockade to durably increase survival against advanced glioblastoma. Clin. Cancer Res. 24, 2559–2573 (2018).

  148. 148.

    Hiniker, S. M., Chen, D. S. & Knox, S. J. Abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 2035; author reply 2035–2036 (2012).

  149. 149.

    Hiniker, S. M. et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol. 5, 404–407 (2012).

  150. 150.

    Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

  151. 151.

    Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

  152. 152.

    Wang, W. et al. IDO immune status after chemoradiation may predict survival in lung cancer patients. Cancer Res. 78, 809–816 (2018). This study reveals strong correlations between high systemic IDO activity in patients with lung cancer (NSCLC) and poor survival prospects after radiochemotherapy.

  153. 153.

    Gyulveszi, G. et al. RG70099: a novel, highly potent dual IDO1/TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment. Cancer Res. 76, LB–085 (2016).

  154. 154.

    Gullapalli, S. et al. EPL-1410, a novel fused heterocycle based orally active dual inhibitor of IDO1/TDO2, as a potential immune-oncology therapeutic. Cancer Res. 78, 1701 (2018).

  155. 155.

    Wang, Y. et al. Preclinical pharmacologic and pharmacodynamic studies of a novel and potent IDO1 inhibitor D-0751. Cancer Res. 78 (Suppl. 13), 2736 (2018).

  156. 156.

    Liu, S. et al. Preclinical evaluation of TQBWX220, a small-molecule inhibitor of IDO1. Cancer Res. 78 (Suppl. 13), 192 (2018).

Download references


Research in the A.L.M. and L.H. laboratory is supported by US National Institutes of Health (NIH) (AI103347), Cancer Research UK and the Faculty of Medical Sciences at Newcastle University. Research in the G.C.P. laboratory is supported by NIH (CA191191), the W.W. Smith Trust, the Lankenau Medical Center Foundation and Main Line Health. G.C.P. is the Havens Chair in Biomedical Research at the Lankenau Institute for Medical Research.

Author information


  1. Institute of Cellular Medicine, Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle-upon-Tyne, UK

    • Henrique Lemos
    • , Lei Huang
    •  & Andrew L. Mellor
  2. Lankenau Institute for Medical Research, Wynnewood, PA, USA

    • George C. Prendergast


  1. Search for Henrique Lemos in:

  2. Search for Lei Huang in:

  3. Search for George C. Prendergast in:

  4. Search for Andrew L. Mellor in:


All authors researched data for the article, substantially contributed to the discussion of content and wrote, reviewed and edited the manuscript.

Competing interests

A.L.M. and G.C.P. receive remuneration as scientific consultants for NewLink Genetics Inc. and are also shareholders in this company. G.C.P. also discloses interests in Incyte as a shareholder and in Kyn Therapeutics as a scientific adviser. A.L.M. also discloses interests as a scientific adviser to Kyn Therapeutics. The other authors declare no competing interests.

Corresponding author

Correspondence to Andrew L. Mellor.


Immune checkpoints

Mechanisms that suppress local immunity in inflamed tissues such as the tumour microenvironment.

Immunological tumour microenvironment

(TME). Primary tumour lesions and local draining lymph nodes where antitumour immunity is controlled.

Integrated stress response

(ISR). A cellular response to stress that impacts protein translation via effects on the eukaryotic initiation factor eIF2.

Damage-associated molecular patterns

(DAMPs). Molecules released by dead and dying cells, which are sensed by innate immune cells.

M2 macrophages

A subset of macrophages typically associated with wound healing and tissue repair.

N-Methyl-d-aspartate receptor signalling

(NMDAR signalling). A signalling pathway that has dichotomous effects on neurons such as promoting death or survival of neurons, resistance to trauma and synaptic plasticity and transmission.

Mechanical nociception

Perception of pain in response to a mechanical stimulus.

About this article

Publication history