IDOはどのようにして免疫反応に影響を及ぼすのでしょうか？
IDOの発現上昇によるT細胞の抑制機序について学ぶ
IDO1
IDO1（Indoleamine 2,3-dioxygenase-1）は、トリプトファンをキヌレニンに代謝し、それによりT細胞の増殖が抑制され、制御性T細胞（Treg）の分化を誘導します。IDO1の阻害により、T細胞の機能が回復し、腫瘍微小環境へのTregの集積が減少する可能性があります。
発現および生理的な機能
- IDO1は抗原提示細胞（APC）で発現する酵素です1,2。
- IDO1の活性化には、補因子の動的な結合が必要です3,4。
- IDO1は、細胞の生存に必須のアミノ酸であるトリプトファンを代謝し、免疫抑制的な作用をもつ代謝産物であるキヌレニン等に変換します1,5。
- 通常、キヌレニンは、T細胞の機能を抑制して過剰な免疫反応を防ぐ、拮抗的なはたらきをしています6,7。
がんでの役割
- 腫瘍では、がん細胞およびAPCの両者でIDO1の発現が増加するようにその環境が変化しており、免疫抑制のプロセスが乗っ取られています1,8-10。
- IDO1の発現上昇によりトリプトファンが欠乏し、キヌレニン濃度が上昇し、これによりT細胞の増殖が抑制され、Tregの分化が誘導され、がん細胞の生存が助長されます11-14。
- IDO1発現の増加は、多くの固形がんおよび造血器腫瘍における予後不良または転帰不良と関連付けられます14-19。
前臨床のエビデンス
- 前臨床試験では、IDO1の阻害により免疫抑制的なTregの数が減少し、細胞傷害性T細胞の機能が回復することが示されています14,20。
- さらに、IDO1阻害と免疫チェックポイント経路の阻害を組み合わせると、相乗的に、T細胞の増殖が亢進し、Tregの集積が減少する可能性があります13,21,22。
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.