Cancer Metabolism

The therapeutic potential of targeting tryptophan catabolism in cancer


Based on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Platten, M., Nollen, E. A. A., Rohrig, U. F., Fallarino, F. & Opitz, C. A. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat. Rev. Drug Discov. 18, 379–401 (2019).

  2. 2.

    Badawy, A. A., Namboodiri, A. M. & Moffett, J. R. The end of the road for the tryptophan depletion concept in pregnancy and infection. Clin. Sci. (Lond). 130, 1327–1333 (2016).

  3. 3.

    Sedlmayr, P., Blaschitz, A. & Stocker, R. The role of placental tryptophan catabolism. Front. Immunol. 5, 230 (2014).

  4. 4.

    Affolter, T., Llewellyn, H. P., Bartlett, D. W., Zong, Q., Xia, S., Torti, V. et al. Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice. PLoS ONE 14, e0217276 (2019).

  5. 5.

    Brenk, M., Scheler, M., Koch, S., Neumann, J., Takikawa, O., Hacker, G. et al. Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells. J. Immunol. 183, 145–154 (2009).

  6. 6.

    Fallarino, F., Grohmann, U., You, S., McGrath, B. C., Cavener, D. R., Vacca, C. et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 176, 6752–6761 (2006).

  7. 7.

    Opitz, C. A., Litzenburger, U. M., Sahm, F., Ott, M., Tritschler, I., Trump, S. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).

  8. 8.

    Gabriely, G. & Quintana, F. J. Role of AHR in the control of GBM-associated myeloid cells. Semin Cancer Biol. (2019). In press.

  9. 9.

    Gutierrez-Vazquez, C. & Quintana, F. J. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 48, 19–33 (2018).

  10. 10.

    Rothhammer, V. & Quintana, F. J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19, 184–197 (2019).

  11. 11.

    Munn, D. H., Zhou, M., Attwood, J. T., Bondarev, I., Conway, S. J., Marshall, B. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998).

  12. 12.

    Hwu, P., Du, M. X., Lapointe, R., Do, M., Taylor, M. W. & Young, H. A. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J. Immunol. 164, 3596–3599 (2000).

  13. 13.

    Munn, D. H., Shafizadeh, E., Attwood, J. T., Bondarev, I., Pashine, A. & Mellor, A. L. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363–1372 (1999).

  14. 14.

    Andersen, M. H. The T-win(R) technology: immune-modulating vaccines. Semin. Immunopathol. 41, 87–95 (2019).

  15. 15.

    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. USA 109, 2497–2502 (2012).

  16. 16.

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

  17. 17.

    Andersen, M. H. The targeting of tumor-associated macrophages by vaccination. Cell Stress. 3, 139–140 (2019).

  18. 18.

    Gibney, G. T., Hamid, O., Lutzky, J., Olszanski, A. J., Mitchell, T. C., Gajewski, T. F. et al. Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma. J. Immunother. Cancer 7, 80 (2019).

  19. 19.

    Gomes, B., Driessens, G., Bartlett, D., Cai, D., Cauwenberghs, S., Crosignani, S. et al. Characterization of the selective indoleamine 2,3-dioxygenase-1 (IDO1) catalytic inhibitor EOS200271/PF-06840003 supports IDO1 as a critical resistance mechanism to PD-(L)1 blockade therapy. Mol. Cancer Ther. 17, 2530–2542 (2018).

  20. 20.

    Mitchell, T. C., Hamid, O., Smith, D. C., Bauer, T. M., Wasser, J. S., Olszanski, A. J. 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).

  21. 21.

    Prendergast, G. C., Mondal, A., Dey, S., Laury-Kleintop, L. D. & Muller, A. J. Inflammatory reprogramming with IDO1 inhibitors: turning immunologically unresponsive ‘cold’ tumors ‘hot’. Trends Cancer. 4, 38–58 (2018).

  22. 22.

    Brochez, L., Chevolet, I. & Kruse, V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur. J. Cancer 76, 167–182 (2017).

  23. 23.

    Jung, K. H., LoRusso, P., Burris, H., Gordon, M., Bang, Y. J., Hellmann, M. D. et al. Phase I study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) administered with PD-L1 inhibitor (atezolizumab) in advanced solid tumors. Clin. Cancer Res. 25, 3220–3228 (2019).

  24. 24.

    Long, G. V., Dummer, R., Hamid, O., Gajewski, T. F., Caglevic, C., Dalle, S. et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 20, 1083–1097 (2019).

  25. 25.

    Honig, A., Rieger, L., Kapp, M., Sutterlin, M., Dietl, J. & Kammerer, U. Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance. J. Reprod. Immunol. 61, 79–86 (2004).

  26. 26.

    Sedlmayr, P. & Blaschitz, A. Placental expression of indoleamine 2,3-dioxygenase. Wien. Med. Wochenschr. 162, 214–219 (2012).

  27. 27.

    Vigneron, N., van Baren, N. & Van den Eynde, B. J. Expression profile of the human IDO1 protein, a cancer drug target involved in tumoral immune resistance. Oncoimmunology 4, e1003012 (2015).

  28. 28.

    Theate, I., van Baren, N., Pilotte, L., Moulin, P., Larrieu, P., Renauld, J. C. 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).

  29. 29.

    Sakurai, K., Amano, S., Enomoto, K., Kashio, M., Saito, Y., Sakamoto, A. et al. [Study of indoleamine 2,3-dioxygenase expression in patients with breast cancer]. Gan to kagaku ryoho Cancer Chemother. 32, 1546–1549 (2005).

  30. 30.

    Hascitha, J., Priya, R., Jayavelu, S., Dhandapani, H., Selvaluxmy, G., Sunder Singh, S. et al. Analysis of kynurenine/tryptophan ratio and expression of IDO1 and 2 mRNA in tumour tissue of cervical cancer patients. Clin. Biochem. 49, 919–924 (2016).

  31. 31.

    Riesenberg, R., Weiler, C., Spring, O., Eder, M., Buchner, A., Popp, T. et al. Expression of indoleamine 2,3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma. Clin. Cancer Res. 13, 6993–7002 (2007).

  32. 32.

    Munn, D. H., Sharma, M. D., Lee, J. R., Jhaver, K. G., Johnson, T. S., Keskin, D. B. et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science. 297, 1867–1870 (2002).

  33. 33.

    Calkins, M. A., Julien, K. & Marti, P. The breakdown of the anelastic approximation in rotating compressible convection: implications for astrophysical systems. Proc. Math. Phys. Eng. Sci. 471, 20140689 (2015).

  34. 34.

    Litzenburger, U. M., Opitz, C. A., Sahm, F., Katharina, J., Trump, S., Winter, 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).

  35. 35.

    Hennequart, M., Pilotte, L., Cane, S., Hoffmann, D., Stroobant, V., Plaen, E. et al. Constitutive IDO1 expression in human tumors is driven by cyclooxygenase-2 and mediates intrinsic immune resistance. Cancer Immunol. Res. 5, 695–709 (2017).

  36. 36.

    Kim, S., Park, S., Cho, M. S., Lim, W., Moon, B. I. & Sung, S. H. Strong correlation of indoleamine 2,3-dioxygenase 1 expression with basal-like phenotype and increased lymphocytic infiltration in triple-negative breast cancer. J. Cancer 8, 124–130 (2017).

  37. 37.

    Yasui, H., Takai, K., Yoshida, R. & Hayaishi, O. Interferon enhances tryptophan metabolism by inducing pulmonary indoleamine 2,3-dioxygenase: its possible occurrence in cancer patients. Proc. Natl Acad. Sci. USA 83, 6622–6626 (1986).

  38. 38.

    Hendrickx, W., Simeone, I., Anjum, S., Mokrab, Y., Bertucci, F., Finetti, P. et al. Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. OncoImmunology 6, e1253654 (2017).

  39. 39.

    Jacquemier, J., Bertucci, F., Finetti, P., Esterni, B., Charafe-Jauffret, E., Thibult, M. L. et al. High expression of indoleamine 2,3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal-like breast carcinoma. Int. J. Cancer 130, 96–104 (2012).

  40. 40.

    Denkert, C., Von Minckwitz, G., Brase, J. C., Sinn, B. V., Gade, S., Kronenwett, R. et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J. Clin. Oncol. 33, 983–991 (2015).

  41. 41.

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

  42. 42.

    Donskov, F. & Von Der Maase, H. Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J. Clin. Oncol. 24, 1997–2005 (2006).

  43. 43.

    Brandacher, G., Perathoner, A., Ladurner, R., Schneeberger, S., Obrist, P., Winkler, C. 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).

  44. 44.

    Ben-Haj-Ayed, A., Moussa, A., Ghedira, R., Gabbouj, S., Miled, S., Bouzid, N. et al. Prognostic value of indoleamine 2,3-dioxygenase activity and expression in nasopharyngeal carcinoma. Immunol. Lett. 169, 23–32 (2016).

  45. 45.

    Ino, K., Yamamoto, E., Shibata, K., Kajiyama, H., Yoshida, N., Terauchi, M. et al. Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin. Cancer Res. 14, 2310–2317 (2008).

  46. 46.

    Inaba, T., Ino, K., Kajiyama, H., Yamamoto, E., Shibata, K., Nawa, A. et al. Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma. Gynecol. Oncol. 115, 185–192 (2009).

  47. 47.

    Carvajal-Hausdorf, D. E., Mani, N., Velcheti, V., Schalper, K. A. & Rimm, D. L. Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancer. J. Immunother. Cancer 5, 81 (2017).

  48. 48.

    Curti, A., Pandolfi, S., Valzasina, B., Aluigi, M., Isidori, A., Ferri, E. et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood 109, 2871–2877 (2007).

  49. 49.

    Witkiewicz, A., Williams, T. K., Cozzitorto, J., Durkan, B., Showalter, S. L., Yeo, C. J. et al. Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J. Am. Coll. Surg. 206, 849–854 (2008).

  50. 50.

    Brody, J. R., Costantino, C. L., Berger, A. C., Sato, T., Lisanti, M. P., Yeo, C. J. 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).

  51. 51.

    Yu, J., Sun, J., Wang, S. E., Li, H., Cao, S., Cong, Y. 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, 469135 (2011).

  52. 52.

    Liu, X. Q., Lu, K., Feng, L. L., Ding, M., Gao, J. M., Ge, X. L. et al. Up-regulated expression of indoleamine 2,3-dioxygenase 1 in non-Hodgkin lymphoma correlates with increased regulatory T-cell infiltration. Leuk. Lymphoma 55, 405–414 (2014).

  53. 53.

    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. 190, 3783–3797 (2013).

  54. 54.

    Holmgaard, R. B., Zamarin, D., Li, Y., Gasmi, B., Munn, D. H., Allison, J. P. et al. Tumor-expressed IDO recruits and activates MDSCs in a treg-dependent manner. Cell Rep. 13, 412–424 (2015).

  55. 55.

    Liu, Y., Liang, X., Dong, W., Fang, Y., Lv, J., Zhang, T. et al. Tumor-repopulating cells induce PD-1 expression in CD8(+) T cells by transferring kynurenine and AhR activation. Cancer Cell 33, 480–94.e7 (2018).

  56. 56.

    Ball, H. J., Sanchez-Perez, A., Weiser, S., Austin, C. J., Astelbauer, F., Miu, J. et al. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene 396, 203–213 (2007).

  57. 57.

    Metz, R., Duhadaway, J. B., Kamasani, U., Laury-Kleintop, L., Muller, A. J. & Prendergast, G. C. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 67, 7082–7087 (2007).

  58. 58.

    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. 192, 1231–1240 (2014).

  59. 59.

    Jusof, F. F. B., Supun, M., Weiser, Silvia, Too, LayKhoon, Metz, Richard, Prendergast, GeorgeC., Fraser, StuartT., Hunt, NicholasH. & Ball, HelenJ. Investigation of the Tissue Distribution and Physiological Roles of Indoleamine 2,3-Dioxygenase-2. Int. J. Tryptophan Res. 10, 1–12 (2017).

  60. 60.

    Metz, R., Smith, C., DuHadaway, J. B., Chandler, P., Baban, B., Merlo, L. M. et al. IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. Int. Immunol. 26, 357–367 (2014).

  61. 61.

    Qian, F., Liao, J., Villella, J., Edwards, R., Kalinski, P., Lele, S. et al. Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation. Cancer Immunol. Immunother. 61, 2013–2020 (2012).

  62. 62.

    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).

  63. 63.

    Liu, Y., Zhang, Y., Zheng, X., Zhang, X., Wang, H., Li, Q. et al. Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+ and inhibits in vivo tumor growth. Oncotarget 7, 32329–32340 (2016).

  64. 64.

    Cancer Genome Atlas Research Network, Weinstein, J. N., Collisson, E. A., Mills, G. B., Shaw, K. R., Ozenberger, B. A. et. al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 45, 1113–1120 (2013).

  65. 65.

    Lob, S., Konigsrainer, A., Zieker, D., Brucher, B. L., Rammensee, H. G., Opelz, G. et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol. Immunother. 58, 153–157 (2009).

  66. 66.

    Corre, S., Tardif, N., Mouchet, N., Leclair, H. M., Boussemart, L., Gautron, A. et al. Sustained activation of the aryl hydrocarbon receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. Nat. Commun. 9, 4775 (2018).

  67. 67.

    Nevler, A., Muller, A. J., Sutanto-Ward, E., DuHadaway, J. B., Nagatomo, K., Londin, E. et al. Host IDO2 gene status influences tumor progression and radiotherapy response in KRAS-driven sporadic pancreatic cancers. Clin. Cancer Res. 25, 724–734 (2019).

  68. 68.

    Witkiewicz, A. K., Costantino, C. L., Metz, R., Muller, A. J., Prendergast, G. C., Yeo, C. J. et al. Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J. Am. Coll. Surg. 208, 781–787 (2009). discussion 7-9.

  69. 69.

    Wu, W., Nicolazzo, J. A., Wen, L., Chung, R., Stankovic, R., Bao, S. S. et al. Expression of tryptophan 2,3-dioxygenase and production of kynurenine pathway metabolites in triple transgenic mice and human Alzheimer’s disease brain. PLoS ONE 8, e59749 (2013).

  70. 70.

    Lanz, T. V., Williams, S. K., Stojic, A., Iwantscheff, S., Sonner, J. K., Grabitz, C. et al. Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis. Sci. Rep. 7, 41271 (2017).

  71. 71.

    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 2, 8 (2009).

  72. 72.

    Miller, C. L., Llenos, I. C., Dulay, J. R., Barillo, M. M., Yolken, R. H. & Weis, S. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol. Dis. 15, 618–629 (2004).

  73. 73.

    GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 45, 580–585 (2013).

  74. 74.

    D’Amato, N. C., Rogers, T. J., Gordon, M. A., Greene, L. I., Cochrane, D. R., Spoelstra, N. S. et al. A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res. 75, 4651–4664 (2015).

  75. 75.

    Novikov, O., Wang, Z., Stanford, E. A., Parks, A. J., Ramirez-Cardenas, A., Landesman, E. et al. An aryl hydrocarbon receptor-mediated amplification loop that enforces cell migration in ER-/PR-/Her2- human breast cancer cells. Mol. Pharmacol. 90, 674–688 (2016).

  76. 76.

    Tina, E., Prosen, S., Lennholm, S., Gasparyan, G., Lindberg, M. & Gothlin Eremo, A. Expression profile of the amino acid transporters SLC7A5, SLC7A7, SLC7A8 and the enzyme TDO2 in basal cell carcinoma. Br. J. Dermatol. 180, 130–140 (2019).

  77. 77.

    Greene, L. I., Bruno, T. C., Christenson, J. L., D’Alessandro, A., Culp-Hill, R., Torkko, K. et al. A role for tryptophan-2,3-dioxygenase in CD8 T-cell suppression and evidence of tryptophan catabolism in breast cancer patient plasma. Mol. Cancer Res. 17, 131–139 (2019).

  78. 78.

    Hao, S., Huang, G., Feng, J., Li, D., Wang, K., Wang, L. et al. Non-NF2 mutations have a key effect on inhibitory immune checkpoints and tumor pathogenesis in skull base meningiomas. J. Neurooncol. 144, 11–20 (2019).

  79. 79.

    Wardhani, L. O., Matsushita, M., Iwasaki, T., Kuwamoto, S., Nonaka, D., Nagata, K. et al. Expression of the IDO1/TDO2-AhR pathway in tumor cells or the tumor microenvironment is associated with Merkel cell polyomavirus status and prognosis in Merkel cell carcinoma. Hum. Pathol. 84, 52–61 (2019).

  80. 80.

    Ott, M., Litzenburger, U. M., Rauschenbach, K. J., Bunse, L., Ochs, K., Sahm, F. et al. Suppression of TDO-mediated tryptophan catabolism in glioblastoma cells by a steroid-responsive FKBP52-dependent pathway. Glia 63, 78–90 (2015).

  81. 81.

    Ochs, K., Ott, M., Rauschenbach, K. J., Deumelandt, K., Sahm, F., Opitz, C. A. et al. Tryptophan-2,3-dioxygenase is regulated by prostaglandin E2 in malignant glioma via a positive signaling loop involving prostaglandin e receptor-4. J. Neurochem. 136, 1142–1154 (2016).

  82. 82.

    Li, S., Zhang, W., Wu, C., Gao, H., Yu, J., Wang, X. et al. HOXC10 promotes proliferation and invasion and induces immunosuppressive gene expression in glioma. FEBS J. 285, 2278–2291 (2018).

  83. 83.

    Pham, Q. T., Oue, N., Sekino, Y., Yamamoto, Y., Shigematsu, Y., Sakamoto, N. et al. TDO2 overexpression is associated with cancer stem cells and poor prognosis in esophageal squamous cell carcinoma. Oncology 95, 297–308 (2018).

  84. 84.

    Munn, D. H., Sharma, M. D., Baban, B., Harding, H. P., Zhang, Y., Ron, D. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 633–642 (2005).

  85. 85.

    Dewhirst, M. W. & Secomb, T. W. Transport of drugs from blood vessels to tumour tissue. Nat. Rev. Cancer 17, 738–750 (2017).

  86. 86.

    Ravishankar, B., Liu, H., Shinde, R., Chaudhary, K., Xiao, W., Bradley, J. 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).

  87. 87.

    Adam, I., Dewi, D. L., Mooiweer, J., Sadik, A., Mohapatra, S. R., Berdel, B. et al. Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation. OncoImmunology 7, e1486353 (2018).

  88. 88.

    Keil, M., Sonner, J. K., Lanz, T. V., Oezen, I., Bunse, T., Bittner, S. et al. General control non-derepressible 2 (GCN2) in T cells controls disease progression of autoimmune neuroinflammation. J. Neuroimmunol. 297, 117–126 (2016).

  89. 89.

    Orsini, H., Araujo, L. P., Maricato, J. T., Guereschi, M. G., Mariano, M., Castilho, B. A. et al. GCN2 kinase plays an important role triggering the remission phase of experimental autoimmune encephalomyelitis (EAE) in mice. Brain Behav. Immun. 37, 177–186 (2014).

  90. 90.

    Sonner, J. K., Deumelandt, K., Ott, M., Thome, C. M., Rauschenbach, K. J., Schulz, S. et al. The stress kinase GCN2 does not mediate suppression of antitumor T cell responses by tryptophan catabolism in experimental melanomas. Oncoimmunology 5, e1240858 (2016).

  91. 91.

    Van de Velde, L. A., Guo, X. J., Barbaric, L., Smith, A. M., Oguin, T. H. 3rd, Thomas, P. G. et al. Stress kinase GCN2 controls the proliferative fitness and trafficking of cytotoxic T cells independent of environmental amino acid sensing. Cell Rep. 17, 2247–2258 (2016).

  92. 92.

    Metz, R., Rust, S., Duhadaway, J. B., Mautino, M. R., Munn, D. H., Vahanian, N. N. 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).

  93. 93.

    Cobbold, S. P., Adams, E., Farquhar, C. A., Nolan, K. F., Howie, D., Lui, K. O. et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc. Natl Acad. Sci. USA 106, 12055–12060 (2009).

  94. 94.

    Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J. & Bradfield, C. A. An Interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).

  95. 95.

    Lowe, M. M., Mold, J. E., Kanwar, B., Huang, Y., Louie, A., Pollastri, M. P. et al. Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production. PLoS ONE 9, e87877 (2014).

  96. 96.

    Stockinger, B., Di Meglio, P., Gialitakis, M. & Duarte, J. H. The aryl hydrocarbon receptor: multitasking in the immune system. Annu. Rev. Immunol. 32, 403–432 (2014).

  97. 97.

    Takenaka, M. C., Gabriely, G., Rothhammer, V., Mascanfroni, I. D., Wheeler, M. A., Chao, C. C. et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat. Neurosci. 22, 729–740 (2019).

  98. 98.

    DiNatale, B. C., Murray, I. A., Schroeder, J. C., Flaveny, C. A., Lahoti, T. S., Laurenzana, E. M. 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).

  99. 99.

    Quintana, F. J., Murugaiyan, G., Farez, M. F., Mitsdoerffer, M., Tukpah, A. M., Burns, E. J. et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 107, 20768–20773 (2010).

  100. 100.

    Li, Q., Harden, J. L., Anderson, C. D. & Egilmez, N. K. Tolerogenic phenotype of IFN-gamma-induced IDO+ dendritic cells is maintained via an autocrine IDO-kynurenine/AhR-IDO loop. J. Immunol. 197, 962–970 (2016).

  101. 101.

    Nguyen, N. T., 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. USA 107, 19961–19966 (2010).

  102. 102.

    Wang, G. Z., Zhang, L., Zhao, X. C., Gao, S. H., Qu, L. W., Yu, H. et al. The aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy. Nat. Commun. 10, 1125 (2019).

  103. 103.

    Sherr, D., Kenison-Whte, J. & Wang, Z. Abstract LB-128: the aryl hydrocarbon receptor as driver of cancer immunity. Cancer Res. 78, LB–128 (2018).

  104. 104.

    Dietrich, C. & Kaina, B. The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth. Carcinogenesis 31, 1319–1328 (2010).

  105. 105.

    Shadboorestan, A., Tarfiei, G. A., Montazeri, H., Sepand, M. R., Zangooei, M., Khedri, A. et al. Invasion and migration of MDA-MB-231 cells are inhibited by block of AhR and NFAT: role of AhR/NFAT1/beta4 integrin signaling. J. Appl. Toxicol. 39, 375–384 (2019).

  106. 106.

    Ye, M., Zhang, Y., Gao, H., Xu, Y., Jing, P., Wu, J. et al. Activation of the aryl hydrocarbon receptor leads to resistance to EGFR TKIs in non-small cell lung cancer by activating Src-mediated bypass signaling. Clin. Cancer Res. 24, 1227–1239 (2018).

  107. 107.

    Chung, W. M., Ho, Y. P., Chang, W. C., Dai, Y. C., Chen, L., Hung, Y. C. et al. Increase paclitaxel sensitivity to better suppress serous epithelial ovarian cancer via ablating androgen receptor/aryl hydrocarbon receptor-ABCG2 axis. Cancers 11, 463 (2019).

  108. 108.

    Wangpaichitr, M., Nguyen, D. J. M., Li, Y.-Y., Wu, C., Feun, L. G. & Savaraj, N. Abstract 4361: kynurenine - aryl hydrocarbon receptor axis: a crucial modulator of immunometabolism in cisplatin resistant lung cancer. Cancer Res. 79, 4361 (2019).

  109. 109.

    Yamashita, N., Kanno, Y., Saito, N., Terai, K., Sanada, N., Kizu, R. et al. Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells. Biochem. Biophys. Res. Commun. 516, 693–698 (2019).

  110. 110.

    Venkateswaran, N., Lafita-Navarro, M. C., Hao, Y. H., Kilgore, J. A., Perez-Castro, L., Braverman, J. et al. MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer. Genes Dev. 33, 1236–1251 (2019).

  111. 111.

    Smith, C., Chang, M. Y., Parker, K. H., Beury, D. W., DuHadaway, J. B., Flick, H. E. et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov. 2, 722–735 (2012).

  112. 112.

    Mondal, A., Smith, C., DuHadaway, J. B., Sutanto-Ward, E., Prendergast, G. C., Bravo-Nuevo, A. et al. IDO1 is an integral mediator of inflammatory neovascularization. EBioMedicine 14, 74–82 (2016).

  113. 113.

    Tang, D., Yue, L., Yao, R., Zhou, L., Yang, Y., Lu, L. et al. P53 prevent tumor invasion and metastasis by down-regulating IDO in lung cancer. Oncotarget 8, 54548–54557 (2017).

  114. 114.

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

  115. 115.

    Pan, K., Wang, H., Chen, M. S., Zhang, H. K., Weng, D. S., Zhou, J. et al. Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma. J. Cancer. Res. Clin. Oncol. 134, 1247–1253 (2008).

  116. 116.

    Liu, X., Wang, M., Jiang, T., He, J., Fu, X. & Xu, Y. IDO1 maintains pluripotency of primed human embryonic stem cells by promoting glycolysis. Stem Cells 37, 1158–1165 (2019).

  117. 117.

    Uyttenhove, C., Pilotte, L., Théate, 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. 9, 1269–1274 (2003).

  118. 118.

    Takamatsu, M., Hirata, A., Ohtaki, H., Hoshi, M., Ando, T., Ito, H. et al. Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice. Cancer Sci. 106, 1008–1015 (2015).

  119. 119.

    Shibata, Y., Hara, T., Nagano, J., Nakamura, N., Ohno, T., Ninomiya, S. et al. The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis. PLoS ONE 11, e0146279 (2016).

  120. 120.

    Schafer, C. C., Wang, Y., Hough, K. P., Sawant, A., Grant, S. C., Thannickal, V. J. et al. Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment. Oncotarget 7, 75407–75424 (2016).

  121. 121.

    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).

  122. 122.

    Hennequart, M., Pilotte, L., Cane, S., Hoffmann, D., Stroobant, V., De Plaen, E. et al. Constitutive IDO1 expression in human tumors is driven by cyclooxygenase-2 and mediates intrinsic immune resistance. Cancer Immunol. Res. 5, 695–710 (2017).

  123. 123.

    Opitz, C. A., Litzenburger, U. M., Lutz, C., Lanz, T. V., Tritschler, I., Koppel, A. et al. Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R. Stem Cells 27, 909–919 (2009).

  124. 124.

    Lanz, T. V., Opitz, C. A., Ho, P. P., Agrawal, A., Lutz, C., Weller, M. et al. Mouse mesenchymal stem cells suppress antigen-specific TH cell immunity independent of indoleamine 2,3-dioxygenase 1 (IDO1). Stem Cells Dev. 19, 657–668 (2010).

  125. 125.

    Meisel, R., Brockers, S., Heseler, K., Degistirici, O., Bulle, H., Woite, C. et al. Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia 25, 648–654 (2011).

  126. 126.

    Prendergast, G. C. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 27, 3889–3900 (2008).

  127. 127.

    van Baren, N. & Van den Eynde, B. J. Tumoral immune resistance mediated by enzymes that degrade tryptophan. Cancer Immunol. Res. 3, 978–985 (2015).

  128. 128.

    Mohinta, S., Kannan, A. K., Gowda, K., Amin, S. G., Perdew, G. H. & August, A. Differential regulation of Th17 and T regulatory cell differentiation by aryl hydrocarbon receptor dependent xenobiotic response element dependent and independent pathways. Toxicol. Sci. 145, 233–243 (2015).

  129. 129.

    Chang, M. Y., Smith, C., DuHadaway, J. B., Pyle, J. R., Boulden, J., Soler, A. P. et al. Cardiac and gastrointestinal liabilities caused by deficiency in the immune modulatory enzyme indoleamine 2,3-dioxygenase. Cancer Biol. Ther. 12, 1050–1058 (2011).

  130. 130.

    Reardon, D., Desjardins, A., Rixe, O., Cloughesy, T., Alekar, S., Gamelin, E. 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-Oncology 19, vi32 (2017).

  131. 131.

    Spranger, S. K., H, K., Horton, B., Scherle, P. A., Newton, R. & Gajewski, T. F. 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 2, 1–14 (2014).

  132. 132.

    Wainwright, D. A., Chang, A. L., Dey, M., Balyasnikova, I. V., Kim, C. K., Tobias, A., Cheng, Y., Kim, J. W., Qiao, J., Zhang, L., Han, Y. & Lesniak, M. S. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4 and PD-L1 in mice with brain tumors. Clin. Cancer Res. 20, 5290–5301 (2014).

  133. 133.

    Toulmonde, M., Penel, N., Adam, J., Chevreau, C., Blay, J. Y., Le Cesne, A. et al. Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas: a phase 2 clinical trial. JAMA Oncol. 4, 93–97 (2017).

  134. 134.

    Zhu, M. M. T., Dancsok, A. R. & Nielsen, T. O. Indoleamine dioxygenase inhibitors: clinical rationale and current development. Curr. Oncol. Rep. 21, 2 (2019).

  135. 135.

    Hamid, O. G., T, F., Frankel, A. E., Bauer, T. M., Olszanski, A. J., Luke, J. J., Balmanoukian, A. S., Schmidt, E. V., Sharkey, B., Maleski, J., Jones, M. J. & Gangadhar, T. C. Epacadostat plus pembrolizumab in patients with advanced melanoma: phase 1 and 2 efficacy and safety results from ECHO-202/KEYNOTE-037. Ann. Oncol. 28, v428–v448 (2017).

  136. 136.

    Gibney, G. T., Hamid, O., Lutzky, J., Olszanski, A. J., Mitchell, T. C., Gajewski, T. F. et. al. Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma. J. Immunother. Cancer 7, 80 (2019).

  137. 137.

    Gangadhar, T. C., Hamid, O., Smith, D. C., Bauer, T. M., Wasser, J. S., Luke, J. J. et al. Preliminary results from a phase I / II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers. J. ImmunoTher. Cancer 3, O7 (2015).

  138. 138.

    Liu, X. S., N, Koblish, H. K., Yang, G., Wang, Q., Wang, K., Leffet, L., Hansbury, M. J., Thomas, B., Rupar, M., Waeltz, P., Bowman, K. J., Polam, P., Sparks, R. B., Yue, E. W., Li, Y., Wynn, R., Fridman, J. S., Burn, T. C., Combs, A. P., Newton, R. C. & Scherle, P. A. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115, 3520–3530 (2010).

  139. 139.

    Spranger, S., Koblish, H. K., Horton, B., Scherle, P. A., Newton, R. & Gajewski, T. F. 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 2, 1–14 (2014).

  140. 140.

  141. 141.

    Beatty, G. L., O'Dwyer, P. J., Clark, J., Shi, J. G., Bowman, K. J., Scherle, P. A. 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. Cancer Ther. Clin. 18, 3269–3277 (2017).

  142. 142.

    Siu, L. L. Gelmon, K., Chu, Q., Pachynski, R., Alese, O., Basciano, P., Walker, J., Mitra, P., Zhu, L., Phillips, P., Hunt, J. & Desai, J. 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, CT116 LP–CT (2017).

  143. 143.

    Fox, E., Oliver, T., Rowe, M., Thomas, S., Zakharia, Y., Gilman, P. B. et al. Indoximod: an immunometabolic adjuvant that empowers T cell activity in cancer. Front. Oncol. 8, 370 (2018).

  144. 144.

    Soliman, H. H., Jackson, E., Neuger, T., Dees, C. E., Harvey, D. R., 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 5, 8136–8146 (2014).

  145. 145.

    Soliman, H. H., Minton, S. E., Han, H. S., Ismail-Khan, R., Neuger, A., Khambati, F. et al. A phase I study of indoximod in patients with advanced malignancies. Oncotarget 7, 22928–22938 (2016).

  146. 146.

    Mautino, M. R., Jaipuri, F. A., Waldo, J., Kumar, S., Adams, J., Van Allen, C. et al. Abstract 491: NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. Cancer Res. 73, 491LP (2013).

  147. 147.

    Nayak-Kapoor, A., Hao, Z., Sadek, R., Dobbins, R., Marshall, L., Vahanian, N. N. 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).

  148. 148.

    Crosignani, S., Bingham, P., Bottemanne, P., Cannelle, H., Cauwenberghs, S., Cordonnier, M. et al. Discovery of a novel and selective indoleamine 2,3-dioxygenase (IDO-1) inhibitor 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and its characterization as a potential clinical candidate. J. Med. Chem. 60, 9617–9629 (2017).

  149. 149.

    Tumang, J., Gomes, B., Wythes, M., Crosignani, S., Bingham, P., Bottemanne, P. et al. Abstract 4863: PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors. Cancer Res. 76, 4863LP (2016).

  150. 150.

    Yap, T. A., Sahebjam, S., Hong, D. S., Chiu, V. K., Yilmaz, E., Efuni, S. et al. First-in-human study of KHK2455, a long-acting, potent and selective indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor, in combination with mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, in patients (pts) with advanced solid tumors. J. Clin. Oncol. 36, 3040 (2018).

  151. 151.

    Dorsey, F. C., Benhadji, K. A., Sams, L. L., Young, D. A., Schindler, J. F., Huss, K. L. et al. Abstract 5245: identification and characterization of the IDO1 inhibitor LY3381916. Cancer Res. 78, 5245 (2018).

  152. 152.

    Mautino, M. R., Kumar, S., Zhuang, H., Waldo, J., Jaipuri, F., Potturi, H. et al. Abstract 4076: A novel prodrug of indoximod with enhanced pharmacokinetic properties. Cancer Res. 77, 4076 (2017).

  153. 153.

    Zhang, Q., Zhang, Y., Boer, J., Shi, J. G., Hu, P., Diamond, S. et al. In vitro interactions of epacadostat and its major metabolites with human efflux and uptake transporters: implications for pharmacokinetics and drug interactions. Drug Metab. Dispos. 45, 612–623 (2017).

  154. 154.

    Zhang, W., Shannon, W. D., Duncan, J., Scheffer, G. L., Scheper, R. J. & McLeod, H. L. Expression of drug pathway proteins is independent of tumour type. J. Pathol. 209, 213–219 (2006).

  155. 155.

    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).

  156. 156.

    Moyer, B. J., Rojas, I. Y., Murray, I. A., Lee, S., Hazlett, H. F., Perdew, G. H. et al. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. Toxicol. Appl. Pharmacol. 323, 74–80 (2017).

  157. 157.

    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).

  158. 158.

    Vogel, C. F., Wu, D., Goth, S. R., Baek, J., Lollies, A., Domhardt, R. et al. Aryl hydrocarbon receptor signaling regulates NF-kappaB RelB activation during dendritic-cell differentiation. Immunol. Cell Biol. 91, 568–575 (2013).

  159. 159.

    Yamamoto, T., Hatabayashi, K., Arita, M., Yajima, N., Takenaka, C., Suzuki, T. et al. Kynurenine signaling through the aryl hydrocarbon receptor maintains the undifferentiated state of human embryonic stem cells. Sci. Signal. 12, eaaw3306 (2019).

  160. 160.

    Monjazeb, A. M., Kent, M. S., Grossenbacher, S. K., Mall, C., Zamora, A. E., Mirsoian, A. et al. Blocking indolamine-2,3-dioxygenase rebound immune suppression boosts antitumor effects of radio-immunotherapy in murine models and spontaneous canine malignancies. Clin. Cancer Res. 22, 4328–4340 (2016).

  161. 161.

    Creelan, B. C., Antonia, S., Bepler, G., Garrett, T. J., Simon, G. R. & Soliman, H. H. Indoleamine 2,3-dioxygenase activity and clinical outcome following induction chemotherapy and concurrent chemoradiation in Stage III non-small cell lung cancer. Oncoimmunology 2, e23428 (2013).

  162. 162.

    Barrero, M. J. Epigenetic strategies to boost cancer immunotherapies. Int. J. Mol. Sci. 18, 1108 (2017).

  163. 163.

    Dewi, D. L., Mohapatra, S. R., Blanco Cabanes, S., Adam, I., Somarribas Patterson, L. F., Berdel, B. et al. Suppression of indoleamine-2,3-dioxygenase 1 expression by promoter hypermethylation in ER-positive breast cancer. Oncoimmunology 6, e1274477 (2017).

  164. 164.

    Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

  165. 165.

    Shapira-Frommer, R., Minei, T. R., Barshack, I., Mendel, I., Yakov, N., Cohen, Y. C. et al. Abstract 4979: Ofranergene Obadenovec (VB-111), an anti-cancer gene therapy, induces immunologic responses in solid tumors transforming cold tumors to hot tumors. Cancer Res. 79, 4979 (2019).

  166. 166.

    Rohrig, U. F., Majjigapu, S. R., 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. 26, 4330–4333 (2016).

  167. 167.

    Ochs, K., Ott, M., Rauschenbach, K. J., Deumelandt, K., Sahm, F., Opitz, C. A. et al. Tryptophan-2,3-dioxygenase is regulated by prostaglandin E2 in malignant glioma via a positive signaling loop involving prostaglandin E receptor-4. J. Neurochem. 136, 1142–1154 (2015).

  168. 168.

    Hashemi Goradel, N., Najafi, M., Salehi, E., Farhood, B. & Mortezaee, K. Cyclooxygenase-2 in cancer: a review. J. Cell. Physiol. 234, 5683–5699 (2019).

  169. 169.

    Tong, D., Liu, Q., Wang, L. A., Xie, Q., Pang, J., Huang, Y. et al. The roles of the COX2/PGE2/EP axis in therapeutic resistance. Cancer Metastasis Rev. 37, 355–368 (2018).

  170. 170.

    Salter, M., Hazelwood, R., Pogson, C. I., Iyer, R. & Madge, D. J. The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat. Biochem. Pharmacol. 49, 1435–1442 (1995).

  171. 171.

    Salter, M., Hazelwood, R., Pogson, C. I., Iyer, R., Madge, D. J., Jones, H. T. et al. The effects of an inhibitor of tryptophan 2,3-dioxygenase and a combined inhibitor of tryptophan 2,3-dioxygenase and 5-HT reuptake in the rat. Neuropharmacology 34, 217–227 (1995).

  172. 172.

    Kozlova, A. & Frederick, R. Current state on tryptophan 2,3-dioxygenase inhibitors: a patent review. Expert Opin. Ther. Pat. 29, 11–23 (2019).

  173. 173.

    Hsu, Y.-L., Hung, J.-Y., Chiang, S.-Y., Jian, S.-F., Wu, C.-Y., Lin, Y.-S. et al. Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis. Oncotarget 7, 27584–27598 (2016).

  174. 174.

    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. 54, 5320–5334 (2011).

  175. 175.

    Gyulveszi, G., Fischer, C., Mirolo, M., Stern, M., Green, L., Ceppi, M. et al. Abstract LB-085: 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).

  176. 176.

    Gullapalli, S., Roychowdhury, A., Khaladkar, T., Sawargave, S., Janrao, R., Kalhapure, V. et al. Abstract 1701: EPL-1410, a novel fused heterocycle based orally active dual inhibitor of IDO1/TDO2, as a potential immuno-oncology therapeutic. Cancer Res. 78, 1701 (2018).

  177. 177.

    Kim, C., Kim, J. H., Kim, J. S., Chon, H. J. & Kim, J.-H. A novel dual inhibitor of IDO and TDO, CMG017, potently suppresses the kynurenine pathway and overcomes resistance to immune checkpoint inhibitors. J. Clin. Oncol. 37, e14228 (2019).

  178. 178.

    Winters, M., DuHadaway, J. B., Pham, K. N., Lewis-Ballester, A., Badir, S., Wai, J. et al. Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase. Eur. J. Med. Chem. 162, 455–464 (2019).

  179. 179.

    Wang, J., Takahashi, R. H., DeMent, K., Gustafson, A., Kenny, J. R., Wong, S. G. et al. Development of a mass spectrometry-based tryptophan 2, 3-dioxygenase assay using liver cytosol from multiple species. Anal. Biochem. 556, 85–90 (2018).

  180. 180.

    Larkin, P. B., Sathyasaikumar, K. V., Notarangelo, F. M., 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 1860, 2345–2354 (2016).

  181. 181.

    Liu, L., Su, X., Quinn III, W. J., Hui, S., Krukenberg, K., Frederick, D. W. et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab. 27, 1067–1080.e5 (2018).

  182. 182.

    Verdin, E. NAD(+) in aging, metabolism, and neurodegeneration. Science 350, 1208–1213 (2015).

  183. 183.

    Tummala, K. S., Gomes, A. L., Yilmaz, M., Grana, O., Bakiri, L., Ruppen, I. et al. Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell 26, 826–839 (2014).

  184. 184.

    Hjortso, M. D., Larsen, S. K., Kongsted, P., Met, O., Frosig, T. M., Andersen, G. H. et al. Tryptophan 2,3-dioxygenase (TDO)-reactive T cells differ in their functional characteristics in health and cancer. Oncoimmunology 4, e968480 (2015).

  185. 185.

    Sorensen, R. B., Berge-Hansen, L., Junker, N., Hansen, C. A., Hadrup, S. R., Schumacher, T. N. et al. The immune system strikes back: cellular immune responses against indoleamine 2,3-dioxygenase. PLoS ONE 4, e6910 (2009).

  186. 186.

    Sorensen, R. B., Hadrup, S. R., Svane, I. M., Hjortso, M. C., Thor Straten, P. & Andersen, M. H. Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators. Blood 117, 2200–2210 (2011).

  187. 187.

    Sorensen, R. B., Kollgaard, T., Andersen, R. S., van den Berg, J. H., Svane, I. M., Straten, P. et al. Spontaneous cytotoxic T-cell reactivity against indoleamine 2,3-dioxygenase-2. Cancer Res. 71, 2038–2044 (2011).

  188. 188.

    Iversen, T. Z., Engell-Noerregaard, L., Ellebaek, E., Andersen, R., Larsen, S. K., Bjoern, J. et al. Long-lasting disease stabilization in the absence of toxicity in metastatic lung cancer patients vaccinated with an epitope derived from indoleamine 2,3 dioxygenase. Clin. Cancer Res. 20, 221–232 (2014).

  189. 189.

    Bjoern, J., Iversen, T. Z., Nitschke, N. J., Andersen, M. H. & Svane, I. M. Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab. Cytotherapy 18, 1043–1055 (2016).

  190. 190.

    Nitschke, N. J., Bjoern, J., Iversen, T. Z., Andersen, M. H. & Svane, I. M. Indoleamine 2,3-dioxygenase and survivin peptide vaccine combined with temozolomide in metastatic melanoma. Stem Cell Investig. 4, 77 (2017).

  191. 191.

    Kjeldsen, J. W., Iversen, T. Z., Engell-Noerregaard, L., Mellemgaard, A., Andersen, M. H. & Svane, I. M. Durable clinical responses and long-term follow-up of stage III-IV non-small-cell lung cancer (NSCLC) patients treated with IDO peptide vaccine in a phase I study-a brief research report. Front. Immunol. 9, 2145 (2018).

  192. 192.

    Cheong, J. E. & Sun, L. Targeting the IDO1/TDO2–KYN–AhR pathway for cancer immunotherapy – challenges and opportunities. Trends Pharmacol. Sci. 38, 307–325 (2018).

  193. 193.

    Triplett, T. A., Garrison, K. C., Marshall, N., Donkor, M., Blazeck, J., Lamb, C. 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).

  194. 194.

    Fukui, S., Schwarcz, R., Rapoport, S. I., Takada, Y. & Smith, Q. R. Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J. Neurochem. 56, 2007–2017 (1991).

  195. 195.

    Guastella, A. R., Michelhaugh, S. K., Klinger, N. V., Kupsky, W. J., Polin, L. A., Muzik, O. et al. Tryptophan PET imaging of the kynurenine pathway in patient-derived xenograft models of glioblastoma. Mol. Imaging 15, 1536012116644881 (2016).

  196. 196.

    Murray, I. A., Patterson, A. D. & Perdew, G. H. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat. Rev. Cancer 14, 801–814 (2014).

  197. 197.

    Pinto, S., Steeneck, C., Albers, M., Anderhub, S., Birkel, M., Buselic-Wölfel, L. et al. Abstract 1210: targeting the IDO1-kynurenine-AhR pathway for cancer immunotherapy. Cancer Res. 79, 1210 (2019).

  198. 198.

    Gentil, M., Hugues, P., Desterke, C., Telliam, G., Sloma, I., Souza, L. E. B. et al. Aryl hydrocarbon receptor (AHR) is a novel druggable pathway controlling malignant progenitor proliferation in chronic myeloid leukemia (CML). PLoS ONE 13, e0200923 (2018).

  199. 199.

    Kim, D., Yoon, S.-S., Shin, D.-Y. Abstract 4675: aryl hydrocarbon receptor antagonist enhances cord blood-derived human hematopoietic stem cell expansion and platelet formation. Cancer Res. 79, 4675 (2019).

  200. 200.

    Scoville, S. D., Nalin, A. P., Chen, L., Chen, L., Zhang, M. H., McConnell, K. et al. Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function. Blood 132, 1792–1804 (2018).

  201. 201.

    Boitano, A. E., Wang, J., Romeo, R., Bouchez, L. C., Parker, A. E., Sutton, S. E. et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345–1348 (2010).

  202. 202.

    Zhao, B., Degroot, D. E., Hayashi, A., He, G. & Denison, M. S. CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor. Toxicol. Sci. 117, 393–403 (2010).

  203. 203.

    Tchaicha, J., Coma, S., Walsh, M., Cavanaugh, J., Sanchez-Martin, M., Zhang, X. M. et al. Abstract 4131: overcoming aryl hydrocarbon receptor mediated tumor immunosuppression. Cancer Res. 79, 4131 (2019).

  204. 204.

    Garcia, C., Lemar, H., Galang, C., Joseph, J., Gonzalez-Lopez, M., Hager, J. et al. Abstract 3255: a novel small molecule inhibitor of AhR suppresses the polarization and activity of M2 macrophages. Cancer Res. 79, 3255 (2019).

  205. 205.

    Gutcher, I., Kober, C., Roese, L., Roewe, J., Schmees, N., Prinz, F. et al. Abstract 1288: blocking tumor-associated immune suppression with BAY-218, a novel, selective aryl hydrocarbon receptor (AhR) inhibitor. Cancer Res. 79, 1288 (2019).

  206. 206.

    Schmees, N., Gutcher, I., Roehn, U., Irlbacher, H., Stoeckigt, D., Bader, B. et al. Abstract 4454: identification of BAY-218, a potent and selective small-molecule AhR inhibitor, as a new modality to counteract tumor immunosuppression. Cancer Res. 79, 4454 (2019).

  207. 207.

    US National Institutes of Health. NCT04069026. Accessed 28 Oct 2019. (2019).

  208. 208.

    Sadok, I., Gamian, A. & Staniszewska, M. M. Chromatographic analysis of tryptophan metabolites. J. Sep. Sci. 40, 3020–3045 (2017).

  209. 209.

    Konishi, M., Ebner, N., Springer, J., Schefold, J. C., Doehner, W., Dschietzig, T. B. et al. Impact of plasma kynurenine level on functional capacity and outcome in heart failure― results from studies investigating co-morbidities aggravating heart failure (SICA-HF). Circ. J. 81, 52–61 (2017).

  210. 210.

    Maliniemi, P., Laukkanen, K., Väkevä, L., Dettmer, K., Lipsanen, T., Jeskanen, L. et al. Biological and clinical significance of tryptophan-catabolizing enzymes in cutaneous T-cell lymphomas. OncoImmunology 6, e1273310 (2017).

  211. 211.

    Reichetzeder, C., Heunisch, F., Einem, G. V., Tsuprykov, O., Kellner, K. H., Dschietzig, T. et al. Pre-interventional kynurenine predicts medium-term outcome after contrast media exposure due to coronary angiography. Kidney Blood Press. Res. 42, 244–256 (2017).

  212. 212.

    Ait-Belkacem, R., Bol, V., Hamm, G., Schramme, F., Van Den Eynde, B., Poncelet, L. et al. Microenvironment tumor metabolic interactions highlighted by qMSI: application to the tryptophan-kynurenine pathway in immuno-oncology. SLAS Discov. 22, 1182–1192 (2017).

  213. 213.

    Giglio, B. C., Fei, H., Wang, M., Wang, H., He, L., Feng, H. et al. Synthesis of 5-[(18)F]Fluoro-alpha-methyl tryptophan: new Trp based PET agents. Theranostics 7, 1524–1530 (2017).

  214. 214.

    Henrottin, J., Lemaire, C., Egrise, D., Zervosen, A., Van den Eynde, B., Plenevaux, A. et al. Fully automated radiosynthesis of N(1)-[(18)F]fluoroethyl-tryptophan and study of its biological activity as a new potential substrate for indoleamine 2,3-dioxygenase PET imaging. Nucl. Med. Biol. 43, 379–389 (2016).

  215. 215.

    Henrottin, J., Zervosen, A., Lemaire, C., Sapunaric, F., Laurent, S., Van den Eynde, B. et al. N (1)-Fluoroalkyltryptophan analogues: synthesis and in vitro study as potential substrates for indoleamine 2,3-dioxygenase. ACS Med. Chem. Lett. 6, 260–265 (2015).

  216. 216.

    Michelhaugh, S. K., Muzik, O., Guastella, A. R., Klinger, N. V., Polin, L. A., Cai, H. et al. Assessment of tryptophan uptake and kinetics using 1-(2-18F-fluoroethyl)-l-tryptophan and alpha-11C-methyl-l-tryptophan PET imaging in mice implanted with patient-derived brain tumor xenografts. J. Nucl. Med. 58, 208–213 (2017).

  217. 217.

    Tang, T., Gill, H. S., Ogasawara, A., Tinianow, J. N., Vanderbilt, A. N., Williams, S. P. et al. Preparation and evaluation of L- and D-5-[(18)F]fluorotryptophan as PET imaging probes for indoleamine and tryptophan 2,3-dioxygenases. Nucl. Med. Biol. 51, 10–17 (2017).

  218. 218.

    Xin, Y. & Cai, H. Improved radiosynthesis and biological evaluations of L- and D-1-[(18)F]fluoroethyl-tryptophan for PET imaging of IDO-mediated kynurenine pathway of tryptophan metabolism. Mol. Imaging Biol. 19, 589–598 (2017).

  219. 219.

    Kimura, R. H., Wang, L., Shen, B., Huo, L., Tummers, W., Filipp, F. V. et al. Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis. Nat. Commun. 10, 4673 (2019).

  220. 220.

    Schmidt, L., Møller, M., Haldrup, C., Strand, S., Vang, S., Hedegaard, J. et al. Exploring the transcriptome of hormone-naive multifocal prostate cancer and matched lymph node metastases. Br. J. Cancer 119, 1527–1537 (2018).

Download references

Author information

C.A.O., L.F.S.P., S.R.M., D.L.D., A.S., M.P. and S.T. collected literature, wrote, read, reviewed and revised the manuscript. L.F.S.P. and S.R.M. conceptualised and prepared the figures in the manuscript.

Correspondence to Christiane A. Opitz.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent to publish

Not applicable.

Data availability

The data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) Project is publicly available.

Competing interests

C.A.O. and M.P. are listed as inventors on the patents “Means and methods for treating and/or preventing natural AHR ligand-dependent cancer” and “Isotopic method for measurement of tryptophan and metabolites thereof”. M.P. is listed on the patent “Treatment of Kynurenine-producing tumors with AHR antagonists”. M.P. has received research support and consulting honoraria from Bayer. The other authors have declared that no competing interests exist.

Funding information

This work was supported by grants from the BMBF e:Med initiative (GlioPATH, 01ZX1402) to S.T. and C.A.O. C.A.O. and A.S. were supported by funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 754688. L.F.S.P. was supported by scholarships from the University of Costa Rica (UCR) and Costa Rica’s Ministry of Science, Technology and Telecommunications (MICITT).

Additional information

Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Opitz, C.A., Somarribas Patterson, L.F., Mohapatra, S.R. et al. The therapeutic potential of targeting tryptophan catabolism in cancer. Br J Cancer 122, 30–44 (2020).

Download citation

Further reading