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Immune control by amino acid catabolism during tumorigenesis and therapy

Abstract

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.

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Fig. 1: Inflammatory and immunological processes during tumorigenesis.
Fig. 2: Inflammatory processes stimulate Trp and Arg catabolism in the TME.
Fig. 3: Immunological and neurological consequences of Trp catabolism relevant to cancer.

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References

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  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.

    Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    PubMed Central  Google Scholar 

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

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  135. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02471846 (2018).

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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. 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).

    PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

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

    Google Scholar 

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Acknowledgements

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.

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

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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.

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Glossary

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.

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Lemos, H., Huang, L., Prendergast, G.C. et al. Immune control by amino acid catabolism during tumorigenesis and therapy. Nat Rev Cancer 19, 162–175 (2019). https://doi.org/10.1038/s41568-019-0106-z

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