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IDO1

Indoleamine 2,3-dioxygenase-1 (IDO1), metabolizes tryptophan into kynurenine, which can suppress T-cell proliferation and promote regulatory T-cell development. Inhibition of IDO1 may restore T-cell function and reduce accumulation of regulatory T cells.

Expression and normal function

IDO1 is an enzyme expressed in antigen-presenting cells (APCs)^1,2
IDO1 activation requires the dynamic binding of its cofactor^3,4

IDO1 metabolizes tryptophan, an amino acid necessary for cell survival, into immunosuppressive metabolites such as kynurenine^1,5
Normally, kynurenine acts as a counterbalance to suppress T-cell function and prevent immune response overactivation^6,7

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Role in cancer

Tumors can evolve to increase IDO1 expression in both tumor cells and APCs, hijacking the immunosuppressive process^1,8-10

IDO1 upregulation depletes tryptophan and generates elevated levels of kynurenine, which suppresses T-cell proliferation and promotes regulatory T-cell (Treg) development, helping tumor cells survive^11-14
Increased IDO1 expression has been associated with poor prognosis and outcomes in many solid tumors and hematologic malignancies^14-19

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Preclinical evidence

In preclinical studies, IDO1 inhibition reduces immunosuppressive Treg numbers and restores cytotoxic T-cell function^14,20

Furthermore, inhibition of both IDO1 and an immune checkpoint pathway may synergistically improve T-cell proliferation and reduce Treg accumulation^13,21,22

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How does IDO impact the immune response?

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REFERENCES–IDO1

1. Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today. 1999;20(10):469-473. 2. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4(10):762-774. 3. Oda S, Sugimoto H, Yoshida T, Shiro Y. Crystallization and preliminary crystallographic studies of human indoleamine 2,3-dioxygenase. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2006;62(Pt 3):221-223. 4. Thomas SR, Salahifar H, Mashima R, Hunt NH, Richardson DR, Stocker R. Antioxidants inhibit indoleamine 2,3-dioxygenase in IFN-γ-activated human macrophages: posttranslational regulation by pyrrolidine dithiocarbamate. J Immunol. 2001;166(10):6332-6340. 5. Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012;72(21):5435-5440. 6. Routy JP, Routy B, Graziani GM, Mehraj V. The kynurenine pathway is a double-edged sword in immune-privileged sites and in cancer: implications for immunotherapy. Int J Tryptophan Res. 2016;9:67-77. 7. Mbongue JC, Nicholas DA, Torrez TW, Kim N-S, Firek AF, Langridge WHR. The role of indoleamine 2, 3-dioxygenase in immune suppression and autoimmunity. Vaccines (Basel). 2015;3(3):703-729. 8. Munn DH, Sharma MD, Hou D, et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest. 2004;114(2):280-290. 9. Liu P, Xie B-L, Cai S-H, et al. Expression of indoleamine 2,3-dioxygenase in nasopharyngeal carcinoma impairs the cytolytic function of peripheral blood lymphocytes. BMC Cancer. 2009. doi:1186/1471-2407-9-416. 10. Löb S, Königsrainer A, Zieker D, et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother. 2009;58(1):153-157. 11. Chen PW, Mellon JK, Mayhew E, et al. Uveal melanoma expression of indoleamine 2,3-deoxygenase: establishment of an immune privileged environment by tryptophan depletion. Exp Eye Res. 2007;85(5):617-625. 12. Munn DH, Sharma MD, Lee JR, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science. 2002;297(5588):1867-1870. 13. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210(7):1389-1402. 14. Wainwright DA, Balyasnikova IV, Chang AL, et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res. 2012;18(22):6110-6121. 15. Folgiero V, Goffredo BM, Filippini P, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia. Oncotarget. 2014;5(8):2052-2064. 16. Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res. 2011;17(22):6985-6991. 17. Jia Y, Wang H, Wang Y, et al. Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients. Int J Cancer. 2015;137(5):1095-1106. 18. Mangaonkar A, Mondal AK, Fulzule S, et al. A novel immunohistochemical score to predict early mortality in acute myeloid leukemia patients based on indoleamine 2,3 dioxygenase expression. Sci Rep. 2017;7(1):12892. doi:10.1038/s41598-017-12940-0. 19. Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer. 2015;3:51. doi:10.1186/s40425-015-0094-9. 20. Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269-1274. 21. Ladomersky E, Zhai L, Lenzen A, et al. IDO1 inhibition synergizes with radiation and PD-1 blockade to durably increase survival against advanced glioblastoma. Clin Cancer Res. 2018;24(11):2559-2573. 22. Sharma MD, Baban B, Chandler P, et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest. 2007;117(9):2570-2582.