吲哚胺2，3-雙加氧酶與腦腫瘤免疫耐受機制的研究進展_《華西醫學》

作者：

李元洋 , 毛伯鏞

南京市中西醫結合醫院（南京，210014）;

關鍵詞：

吲哚胺2，3-雙加氧酶腦腫瘤免疫耐受膠質瘤

DOI：

10.7507/1002-0179.20130461

視頻：

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摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

吲哚胺2，3-雙加氧酶（IDO）是一種色氨酸代謝初期的限速酶，研究表明免疫抑制劑IDO的表達可誘導腫瘤的免疫耐受，導致腫瘤無限制生長。通過回顧分析多項有關IDO在人類惡性腫瘤及中樞神經系統（CNS）腫瘤中的相關臨床研究資料，研究發現抑制IDO的誘導作用會阻礙腫瘤的生長，阻斷IDO經犬尿酸途徑誘導的色氨酸耗竭過程會抑制腫瘤細胞增殖，同時提高腫瘤的免疫治療效果。然而，IDO誘導的色氨酸代謝在CNS腫瘤免疫耐受中的作用機制目前尚不明確。深入研究IDO在CNS腫瘤中的免疫耐受作用機制具有重要意義，因此IDO抑制劑有望成為生物治療腦腫瘤的重要手段之一。

引用本文： 李元洋,毛伯鏞. 吲哚胺2，3-雙加氧酶與腦腫瘤免疫耐受機制的研究進展. 華西醫學, 2013, 28(9): 1472-1475. doi: 10.7507/1002-0179.20130461 復制

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3.	Soliman H, Mediavilla-Varela M, Antonia S. Indoleamine 2,3-dioxygenase is it an immune suppressor[J]. J Cancer, 2010, 16(4): 354–359.
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5.	Munn DH, Sharma MD, Baban B, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase[J]. Immunity, 2005, 22(5): 633-642.
6.	Sharma MD, Hou DY, Baban B, et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice[J]. Immunity, 2010, 33(6): 942-954.
7.	Li Y, Tredget EE, Ghahary A. Cell surface expression of MHC class I antigen is suppressed in indoleamine 2,3-dioxygenase genetically modified keratinocytes: implications in allogeneic skin substitute engraftment[J]. Hum Immunol, 2004, 65(2): 114-123.
8.	Shields JD, Kourtis IC, Tomei AA, et al. Induction of lymphoidlike stroma and immune escape by tumors that Express the chemokine CCL21[J]. Science, 2010, 328(5979): 749-752.
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13.	Sa QD, Peggs KS, Simpson TR, et al. Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication[J]. Immunol Rev, 2011, 241(1): 104-118.
14.	Zhai H, Heppner FL, Tsirka SE. Microglia/macrophages promote glioma progression[J]. Glia, 2011, 59(3): 472-485.
15.	Fletcher AL, Malhotra D, Turley SJ. Lymph node stroma broaden the peripheral tolerance paradigm[J]. Trends Immunol, 2011, 32(1): 12-18.
16.	Fabry Z, Schreiber HA, Harris MG, et al. Sensing the microenvironment of the central nervous system: immune cells in the central nervous system and their pharmacological manipulation[J]. Curr Opin Pharmacol, 2008, 8(4): 496-507.
17.	Kaur G, Han SJ, Yang I, et al. Microglia and central nervous system immunity[J]. Neurosurg Clin N Am, 2010, 21(1): 43-51.
18.	Wesolowska A, Kwiatkowska A, Slomnicki L, et al. Microglia-derived TGF-β as an important regulator of glioblastoma invasion-an inhibition of TGF-β-dependent effects by shRNA against human TGF-β typeⅡ receptor[J]. Oncogene, 2008, 27(7): 918-930.
19.	Merzak A, McCrea S, Koocheckpour S, et al. Control of human glioma cell growth, migration and invasion in vitro by transforming growth factor beta 1[J]. Br J Cancer, 1994, 70(2): 199-203.
20.	Wick W, Platten M, Weller M. Glioma cell invasion: regulation of metalloproteinase activity by TGF-β[J]. J Neurooncol, 2001, 53(2): 177-185.
21.	Wu A, Wei J, Kong LY, et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia[J]. Neuro Oncol, 2010, 12(11): 1113-1125.
22.	Inaba T, Ino K, Kajiyama H, et al. Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma[J]. Gynecol Oncol, 2009, 115(2): 185-192.
23.	Nakamura T, Shima T, Saeki A, et al. Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer[J]. Cancer Sci, 2007, 98(6): 874-881.
24.	Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells[J]. Clin Cancer Res, 2006, 12(4): 1144-1151.
25.	Ino K, Yoshida N, Kajiyama H, et al. Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer[J]. Br J Cancer, 2006, 95(11): 1555-1561.
26.	Pan K, Wang H, Chen MS, et al. Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2008, 134(11): 1247-1253.
27.	Ishio T, Goto S, Tahara K, et al. Immunoactivative role of indoleamine 2,3-dioxygenase in human hepatocellular carcinoma[J]. J Gastroenterol Hepatol, 2004, 19(3): 319-326.
28.	Riesenberg R, Weiler C, Spring O, et al. Expression of indoleamine 2,3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma[J]. Clin Cancer Res, 2007, 13(23): 6993-7002.
29.	Batista CE, Juhász C, Muzik O, et al. Imaging correlates of differential expression of indoleamine 2,3-dioxygenase in human brain tumors[J]. Mol Imaging Biol, 2009, 11(6): 460-466.
30.	Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase[J]. Nat Med, 2003, 9(10): 1269-1274.
31.	Wolff JE, Wagner S, Reinert C, et al. Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma[J]. J Neurooncol, 2006, 79(3): 315-321.
32.	Miyazaki T, Moritake K, Yamada K, et al. Indoleamine 2,3-dioxygenase as a new target for malignant glioma therapy. Laboratory investigation[J]. J Neurosurg, 2009, 111(2): 230-237.

1. 　Lai A, Tran A, Nghiemphu PL, et al. Phase Ⅱ study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme[J]. J Clin Oncol, 2011, 29(2): 142-148.
2. 　Baban B, Chandler PR, Sharma MD, et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells[J]. J Immunol, 2009, 183(4): 2475-2483.
3. 　Soliman H, Mediavilla-Varela M, Antonia S. Indoleamine 2,3-dioxygenase is it an immune suppressor[J]. J Cancer, 2010, 16(4): 354–359.
4. 　Yan Y, Zhang GX, Gran B, et al. IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis[J]. J Immunol, 2010, 185(10): 5953-5961.
5. 　Munn DH, Sharma MD, Baban B, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase[J]. Immunity, 2005, 22(5): 633-642.
6. 　Sharma MD, Hou DY, Baban B, et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice[J]. Immunity, 2010, 33(6): 942-954.
7. 　Li Y, Tredget EE, Ghahary A. Cell surface expression of MHC class I antigen is suppressed in indoleamine 2,3-dioxygenase genetically modified keratinocytes: implications in allogeneic skin substitute engraftment[J]. Hum Immunol, 2004, 65(2): 114-123.
8. 　Shields JD, Kourtis IC, Tomei AA, et al. Induction of lymphoidlike stroma and immune escape by tumors that Express the chemokine CCL21[J]. Science, 2010, 328(5979): 749-752.
9. 　Llambi F, Green DR. Apoptosis and oncogenesis: give and take in the BCL-2 family[J]. Curr Opin Genet Dev, 2011, 21(1): 12-20.
10. 　Ribechini E, Greifenberg V, Sandwick S, et al. Subsets, expansion and activation of myeloid-derived suppressor cells[J]. Med Microbiol Immunol, 2010, 199(3): 273-281.
11. 　Movahedi K, Laoui D, Gysemans C, et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C (high) monocytes[J]. Cancer Res, 2010, 70(14): 5728-5739.
12. 　Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion[J]. Science, 2011, 331(6024): 1565-1570.
13. 　Sa QD, Peggs KS, Simpson TR, et al. Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication[J]. Immunol Rev, 2011, 241(1): 104-118.
14. 　Zhai H, Heppner FL, Tsirka SE. Microglia/macrophages promote glioma progression[J]. Glia, 2011, 59(3): 472-485.
15. 　Fletcher AL, Malhotra D, Turley SJ. Lymph node stroma broaden the peripheral tolerance paradigm[J]. Trends Immunol, 2011, 32(1): 12-18.
16. 　Fabry Z, Schreiber HA, Harris MG, et al. Sensing the microenvironment of the central nervous system: immune cells in the central nervous system and their pharmacological manipulation[J]. Curr Opin Pharmacol, 2008, 8(4): 496-507.
17. 　Kaur G, Han SJ, Yang I, et al. Microglia and central nervous system immunity[J]. Neurosurg Clin N Am, 2010, 21(1): 43-51.
18. 　Wesolowska A, Kwiatkowska A, Slomnicki L, et al. Microglia-derived TGF-β as an important regulator of glioblastoma invasion-an inhibition of TGF-β-dependent effects by shRNA against human TGF-β typeⅡ receptor[J]. Oncogene, 2008, 27(7): 918-930.
19. 　Merzak A, McCrea S, Koocheckpour S, et al. Control of human glioma cell growth, migration and invasion in vitro by transforming growth factor beta 1[J]. Br J Cancer, 1994, 70(2): 199-203.
20. 　Wick W, Platten M, Weller M. Glioma cell invasion: regulation of metalloproteinase activity by TGF-β[J]. J Neurooncol, 2001, 53(2): 177-185.
21. 　Wu A, Wei J, Kong LY, et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia[J]. Neuro Oncol, 2010, 12(11): 1113-1125.
22. 　Inaba T, Ino K, Kajiyama H, et al. Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma[J]. Gynecol Oncol, 2009, 115(2): 185-192.
23. 　Nakamura T, Shima T, Saeki A, et al. Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer[J]. Cancer Sci, 2007, 98(6): 874-881.
24. 　Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells[J]. Clin Cancer Res, 2006, 12(4): 1144-1151.
25. 　Ino K, Yoshida N, Kajiyama H, et al. Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer[J]. Br J Cancer, 2006, 95(11): 1555-1561.
26. 　Pan K, Wang H, Chen MS, et al. Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2008, 134(11): 1247-1253.
27. 　Ishio T, Goto S, Tahara K, et al. Immunoactivative role of indoleamine 2,3-dioxygenase in human hepatocellular carcinoma[J]. J Gastroenterol Hepatol, 2004, 19(3): 319-326.
28. 　Riesenberg R, Weiler C, Spring O, et al. Expression of indoleamine 2,3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma[J]. Clin Cancer Res, 2007, 13(23): 6993-7002.
29. 　Batista CE, Juhász C, Muzik O, et al. Imaging correlates of differential expression of indoleamine 2,3-dioxygenase in human brain tumors[J]. Mol Imaging Biol, 2009, 11(6): 460-466.
30. 　Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase[J]. Nat Med, 2003, 9(10): 1269-1274.
31. 　Wolff JE, Wagner S, Reinert C, et al. Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma[J]. J Neurooncol, 2006, 79(3): 315-321.
32. 　Miyazaki T, Moritake K, Yamada K, et al. Indoleamine 2,3-dioxygenase as a new target for malignant glioma therapy. Laboratory investigation[J]. J Neurosurg, 2009, 111(2): 230-237.

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吲哚胺2，3-雙加氧酶與腦腫瘤免疫耐受機制的研究進展

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