IDO在肿瘤中作用的研究进展
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摘要
肿瘤有特异性的肿瘤抗原,能诱导机体产生抗肿瘤作用的免疫应答。但是自然状态下有时免疫系统不能有效地控制肿瘤的发生发展,主要是因为肿瘤微环境中产生了针对肿瘤抗原的免疫耐受,即免疫活性细胞接触肿瘤抗原性物质时所表现的一种特异性无应答状态。最新的研究证实吲哚胺-2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)的过度表达导致的色氨酸代谢异常在肿瘤患者的免疫耐受中发挥了重要作用。肿瘤患者体内的IDO表达上调,通过一系列复杂的机制抑制肿瘤微环境中的抗肿瘤免疫反应,促进肿瘤血管生成。抑制IDO的活性则可以打破免疫耐受,增强抗肿瘤免疫反应。IDO及色氨酸代谢产物犬尿氨酸还可以作为肿瘤患者预后的预测因子。
Sometimes malignant tumors are initiated and developed because of the immune tolerance,that is the immune system fails to response to tumor specific antigens or unresponsiveness.Recent studies have revealed that the metabolic abnormality induced by the overexpression of indoleamine 2,3-dioxygenase(IDO) plays an important role in immune tolerance of cancer patients,which involving a series of mechanisms including inhibiting immune response and promoting tumor angiogenesis. On the contrary,inhibiting the activity of IDO can break immune tolerance and enhance antitumor response. The serum levels of IDO can be used a prognostic marker for tumor patients,as well as the serum concentration of tryptophan metabolite kynurenine.
Sometimes malignant tumors are initiated and developed because of the immune tolerance,that is the immune system fails to response to tumor specific antigens or unresponsiveness.Recent studies have revealed that the metabolic abnormality induced by the overexpression of indoleamine 2,3-dioxygenase(IDO) plays an important role in immune tolerance of cancer patients,which involving a series of mechanisms including inhibiting immune response and promoting tumor angiogenesis. On the contrary,inhibiting the activity of IDO can break immune tolerance and enhance antitumor response. The serum levels of IDO can be used a prognostic marker for tumor patients,as well as the serum concentration of tryptophan metabolite kynurenine.
引文
[1]Trott JF,Kim J,Abu AO,et al.Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer[J].Oncotarget,2016,7(41):66540-66557.
[2]Munn DH,Mellor AL.IDO in the tumor microenvironment:inflammation,counter-regulation,and tolerance[J].Trends immunol,2016,37(3):193-207.
[3]Nonaka H,Saga Y,Fujiwara H,et al.Indoleamine 2,3-dioxygenase promotes peritoneal dissemination of ovarian cancer through inhibition of natural killer cell function and angiogenesis promotion[J].Int J Oncol,2011,38(1):113-120.
[4]Schafer CC,Wang Y,Hough KP,et al.Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment[J].Oncotarget,2016,7(46):75407-75424.
[5]Lindstrom V,Aittoniemi J,Eklund C,et al.Indoleamine2,3-dioxygenase activity and expression in patients with chronic lymphocytic leukemia[J].Clin Lymphoma Myeloma Leuk,2012,12(5):363-365.
[6]Mabuchi R,Hara T,Matsumoto T,et al.High serum concentration of L-kynurenine predicts unfavorable outcomes in patients with acute myeloid leukemia[J].Leuk Lymphoma,2016,57(1):92-98.
[7]Shibata Y,Hara T,Nagano J,et al.The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis[J].PLo S One,2016,11(1):e014627
[8]Zuo H,Ueland PM,Ulvik A,et al.Plasma biomarkers of inflammation,the kynurenine pathway,and risks of allcause,cancer,and cardiovascular disease mortality:the hordaland health study[J].Am J Epidemiol,2016,183(4):249-258.
[9]Yong WM,Joud H,Patrick H,et al.Targeting the indoleamine 2,3-dioxygenase pathway in cancer[J].Immunother Cancer,2015,3:51.
[10]Routy JP,Routy B,Graziani GM,et al.The kynurenine pathway is a double-edged sword in immune-privileged sites and in cancer:implications for immunotherapy[J].Int J Ttryptophan Res,2016,9:67-77.
[11]Prendergast GC.Why tumor eat tryptophan[J].Nature,2011,478(7368):192-194.
[12]Boitano AE,Wang J,Romeo R,et al.Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells[J].Science,2010,329(5997):1345-1348.
[13]Balachandran VP,Cavnar MJ,Zeng S,et al.Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido[J].Nat Med,2011,17(9):1094-1100.
[14]Munn DH,Mellor AL.Indoleamine 2,3 dioxygenase and metabolic control of immune responses[J].Trends Immunol,2013,34(3):137-143.
[15]Ravishankar B,Liu H,Shinde R,et al.The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity[J].Proc Natl Acad Sci USA,2015,112(34):10774-10779.
[16]Dagenais-Lussier X,Aounallah M,Mehraj V,et al.Kynurenine reduces memory CD4 T-Cell survival by interfering with interleukin-2 signaling early during HIV-1Infection[J].Virol,2016,90(17):7967-7979.
[17]Dons EM,Raimondi G,Cooper DK,et al.Induced regulatory T cells:mechanisms of conversion and suppressive potential[J].Hum Immunol,2012,73(4):328-334.
[18]Harden JL,Egilmez NK.Indoleamine 2,3-dioxygenase and dendritic cell tolerogenicity[J].Immunol Invest,2012,41(6-7):738-764.
[19]Li R,Li H,Sun Q,et al.Indoleamine 2,3-dioxygenase regulates T cell activity through Vav1/Rac pathway[J].Mol Immunol,2017,81:102-107.
[20]Li RM,Wei F,Yu JP,et al.The role of Vav1 in T cells suppressed by indoleamine 2,3-dioxygenase[J].Chinese Journal of Immunology,2009,25(9):786-791.[李润美,魏枫,于津浦,等.Vav1在吲哚胺2,3双加氧酶抑制T细胞中的作用初探[J].中国免疫学杂志,2009,25(9):786-791.]
[21]Holmgaard RB,Zamarin D,Li Y,et al.Tumor-expressed I-DO recruits and activates MDSCs in a Treg-dependent manner[J].Cell Rep,2015,13(2):412-424.
[22]Yu J,Du W,Yan F,et al.Myeloid-derived suppressor cells suppress antitumor immune responses through IDOexpression and correlate with lymph node metastasis in patients with breast cancer[J].J Immunol,2013,190(7):3783-3797.
[23]Jitschin R,Braun M,Buttner M,et al.CLL-cells induce I-DOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote Tregs[J].Blood,2014,124(5):750-760.
[24]Zhang H,Maric I,Di Prima MJ,et al.Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer[J].Blood,2013,122(7):1105-1113.
[25]Peng YP,Zhang JJ,Liang WB,et al.Elevation of MMP-9and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction[J].BMC Cancer,2014,14:738.
[26]Ravishankar B,Liu H,Shinde R,et al.Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase[J].Proc Natl Acad Sci USA,2012,109(10):3909-3914.
[27]Liu H,Huang L,Bradley J,et al.GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology[J].Mol Cell Biol,2014,34(3):428-438.
[28]Liu W,Xie S,Chen X,et al.Activation of the IL-6/JAK/STAT3 signaling pathway in human middle ear cholesteatoma epithelium[J].Int J Clin Exp Pathol,2014,7(2):709-715.
[29]Ploder M,Spittler A,Kurz K,et al.Accelerated tryptophan degradation predicts poor survival in trauma and sepsis patients[J].Int J Tryptophan Res,2010,3:61-67.
[30]Sperner-Unterweger B,Neurauter G,Klieber M,et al.Enhanced tryptophan degradation in patients with ovarian carcinoma correlates with several serum soluble immune activation markers[J].Immunobiology,2011,216(3):296-301.
[31]Zhou Y,Liu CH,Zhou LX,et al.Resonant raman spectra of grades of human brain glioma tumors reveal the content of tryptophan by the 1588cm-1mode[A].Alfano RR,Demoss G.SPIE Proceedings Vol.9318:optical biosyⅩⅢ:toward real-time spectroscopic imaging and diagnosis[C].Bellingham:SPIE,2015.
[32]de Lecea MV,Palomares T,Al Kassam D,et al.Indoleamine 2,3 dioxygenase as a prognostic and follow-up marker in melanoma:a comparative study with LDH and S100B[J].J Eur Acad Dermatol Venereol,2017,31(4):636-642.
[33]Zhang T,Tan XL,Xu Y,et al.Expression and prognostic value of indoleamine 2,3-dioxygenase in pancreatic cancer[J].Chin Med J(Engl),2017,130(6):710-716.
[34]Ogawa M,Watanabe M,Hasegawa T,et al.Expression of CXCR-4 and IDO in human colorectal cancer:an immunohistochemical approach[J].Mol Clin Oncol,2017,6(5):701-704.
[35]Tang D,Yue L,Yao R,et al.P53 prevent tumor invasion and metastasis by down-regulating IDO in lung cancer[J].Oncotarget,2017.[Epub ahead of print]
[36]Heng B,Lim CK,Lovejoy DB,et al.Understanding the role of the kynurenine pathway in human breast cancer immunobiology[J].Oncotarget,2016,7(6):6506-6520.
[37]Asghar K,Farooq A,Zulfiqar B,et al.Indoleamine 2,3-dioxygenase:as a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma[J].World J Gastroenterol,2017,23(13):2286-2293.
[38]Pschowski R,Pape UF,Fusch G,et al.Increased activity of the immunoregulatory enzyme indoleamine-2,3-Dioxygenase with consecutive tryptophan depletion predicts death in patients with neuroendocrine neoplasia[J].Neuroendocrinology,2017,104(2):135-144.
[39]Hudolin T,Mengus C,Coulot J,et al.Expression of indoleamine 2,3-dioxygenase gene is a feature of poorly differentiated non-muscle-invasive urothelial cell bladder carcinomas[J].Anticancer Res,2017,37(3):1375-1380.
[40]Li M,Bolduc AR,Hoda MN,et al.The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma[J].Immunother Cancer,2014,2:21.
[41]Meng X,Du G,Ye L,et al.Combinatorial antitumor effects of indoleamine 2,3-dioxygenase inhibitor NLG919 and paclitaxel in a murine B16-F10 melanoma model[J].Int JImmunopathol Pharmacol,2017,30(3):215-226.
[42]Liu KT,Liu YH,Liu HL,et al.Neutrophils are essential in short hairpin RNA of indoleamine 2,3-dioxygenase mediated-antitumor efficiency[J].Mol Ther Nucleic Acids,2016,5(12):e397.
[43]Holmgaard RB,Zamarin D,Munn DH,et al.Indoleamine2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4[J].Exp Med,2013,210(7):1389-1402.
[44]Gangadhar TC,Hamid O,Smith DC,et al.Preliminary results from a phaseⅠ/Ⅱstudy of epacadostat(incb024360)in combination with pembrolizumab in patients with selected advanced cancers[J].J Immunother Cancer,2015,3(Suppl 2):7.
[45]Bilal Z,Amnah M,Kaenat N,et al.Nanomedicine and cancer immunotherapy:focus on indoleamine 2,3-dioxygenase inhibitors[J].Oncol Targets Ther,2017,10:463-476.
[46]Ogawa K,Hara T,Shimizu M,et al.(-)-Epigallocatechin gallate inhibits the expression of indoleamine 2,3-dioxygenase in human colorectal cancer cells[J].Oncol Lett,2012,4(3):546-550.
[47]Prendergast GC,Smith C,Thomas S,et al.Indoleamine2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer[J].Cancer Immunol Immunother,2014,63(7):721-735.
[48]Soliman HH,Jackson E,Neuger T,et al.A first in man phaseⅠtrial of the oral immunomodulator,indoximod,combined with docetaxel in patients with metastatic solid tumors[J].Oncotarget,2014,5(18):8136-8146.
[2]Munn DH,Mellor AL.IDO in the tumor microenvironment:inflammation,counter-regulation,and tolerance[J].Trends immunol,2016,37(3):193-207.
[3]Nonaka H,Saga Y,Fujiwara H,et al.Indoleamine 2,3-dioxygenase promotes peritoneal dissemination of ovarian cancer through inhibition of natural killer cell function and angiogenesis promotion[J].Int J Oncol,2011,38(1):113-120.
[4]Schafer CC,Wang Y,Hough KP,et al.Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment[J].Oncotarget,2016,7(46):75407-75424.
[5]Lindstrom V,Aittoniemi J,Eklund C,et al.Indoleamine2,3-dioxygenase activity and expression in patients with chronic lymphocytic leukemia[J].Clin Lymphoma Myeloma Leuk,2012,12(5):363-365.
[6]Mabuchi R,Hara T,Matsumoto T,et al.High serum concentration of L-kynurenine predicts unfavorable outcomes in patients with acute myeloid leukemia[J].Leuk Lymphoma,2016,57(1):92-98.
[7]Shibata Y,Hara T,Nagano J,et al.The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis[J].PLo S One,2016,11(1):e014627
[8]Zuo H,Ueland PM,Ulvik A,et al.Plasma biomarkers of inflammation,the kynurenine pathway,and risks of allcause,cancer,and cardiovascular disease mortality:the hordaland health study[J].Am J Epidemiol,2016,183(4):249-258.
[9]Yong WM,Joud H,Patrick H,et al.Targeting the indoleamine 2,3-dioxygenase pathway in cancer[J].Immunother Cancer,2015,3:51.
[10]Routy JP,Routy B,Graziani GM,et al.The kynurenine pathway is a double-edged sword in immune-privileged sites and in cancer:implications for immunotherapy[J].Int J Ttryptophan Res,2016,9:67-77.
[11]Prendergast GC.Why tumor eat tryptophan[J].Nature,2011,478(7368):192-194.
[12]Boitano AE,Wang J,Romeo R,et al.Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells[J].Science,2010,329(5997):1345-1348.
[13]Balachandran VP,Cavnar MJ,Zeng S,et al.Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido[J].Nat Med,2011,17(9):1094-1100.
[14]Munn DH,Mellor AL.Indoleamine 2,3 dioxygenase and metabolic control of immune responses[J].Trends Immunol,2013,34(3):137-143.
[15]Ravishankar B,Liu H,Shinde R,et al.The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity[J].Proc Natl Acad Sci USA,2015,112(34):10774-10779.
[16]Dagenais-Lussier X,Aounallah M,Mehraj V,et al.Kynurenine reduces memory CD4 T-Cell survival by interfering with interleukin-2 signaling early during HIV-1Infection[J].Virol,2016,90(17):7967-7979.
[17]Dons EM,Raimondi G,Cooper DK,et al.Induced regulatory T cells:mechanisms of conversion and suppressive potential[J].Hum Immunol,2012,73(4):328-334.
[18]Harden JL,Egilmez NK.Indoleamine 2,3-dioxygenase and dendritic cell tolerogenicity[J].Immunol Invest,2012,41(6-7):738-764.
[19]Li R,Li H,Sun Q,et al.Indoleamine 2,3-dioxygenase regulates T cell activity through Vav1/Rac pathway[J].Mol Immunol,2017,81:102-107.
[20]Li RM,Wei F,Yu JP,et al.The role of Vav1 in T cells suppressed by indoleamine 2,3-dioxygenase[J].Chinese Journal of Immunology,2009,25(9):786-791.[李润美,魏枫,于津浦,等.Vav1在吲哚胺2,3双加氧酶抑制T细胞中的作用初探[J].中国免疫学杂志,2009,25(9):786-791.]
[21]Holmgaard RB,Zamarin D,Li Y,et al.Tumor-expressed I-DO recruits and activates MDSCs in a Treg-dependent manner[J].Cell Rep,2015,13(2):412-424.
[22]Yu J,Du W,Yan F,et al.Myeloid-derived suppressor cells suppress antitumor immune responses through IDOexpression and correlate with lymph node metastasis in patients with breast cancer[J].J Immunol,2013,190(7):3783-3797.
[23]Jitschin R,Braun M,Buttner M,et al.CLL-cells induce I-DOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote Tregs[J].Blood,2014,124(5):750-760.
[24]Zhang H,Maric I,Di Prima MJ,et al.Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer[J].Blood,2013,122(7):1105-1113.
[25]Peng YP,Zhang JJ,Liang WB,et al.Elevation of MMP-9and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction[J].BMC Cancer,2014,14:738.
[26]Ravishankar B,Liu H,Shinde R,et al.Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase[J].Proc Natl Acad Sci USA,2012,109(10):3909-3914.
[27]Liu H,Huang L,Bradley J,et al.GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology[J].Mol Cell Biol,2014,34(3):428-438.
[28]Liu W,Xie S,Chen X,et al.Activation of the IL-6/JAK/STAT3 signaling pathway in human middle ear cholesteatoma epithelium[J].Int J Clin Exp Pathol,2014,7(2):709-715.
[29]Ploder M,Spittler A,Kurz K,et al.Accelerated tryptophan degradation predicts poor survival in trauma and sepsis patients[J].Int J Tryptophan Res,2010,3:61-67.
[30]Sperner-Unterweger B,Neurauter G,Klieber M,et al.Enhanced tryptophan degradation in patients with ovarian carcinoma correlates with several serum soluble immune activation markers[J].Immunobiology,2011,216(3):296-301.
[31]Zhou Y,Liu CH,Zhou LX,et al.Resonant raman spectra of grades of human brain glioma tumors reveal the content of tryptophan by the 1588cm-1mode[A].Alfano RR,Demoss G.SPIE Proceedings Vol.9318:optical biosyⅩⅢ:toward real-time spectroscopic imaging and diagnosis[C].Bellingham:SPIE,2015.
[32]de Lecea MV,Palomares T,Al Kassam D,et al.Indoleamine 2,3 dioxygenase as a prognostic and follow-up marker in melanoma:a comparative study with LDH and S100B[J].J Eur Acad Dermatol Venereol,2017,31(4):636-642.
[33]Zhang T,Tan XL,Xu Y,et al.Expression and prognostic value of indoleamine 2,3-dioxygenase in pancreatic cancer[J].Chin Med J(Engl),2017,130(6):710-716.
[34]Ogawa M,Watanabe M,Hasegawa T,et al.Expression of CXCR-4 and IDO in human colorectal cancer:an immunohistochemical approach[J].Mol Clin Oncol,2017,6(5):701-704.
[35]Tang D,Yue L,Yao R,et al.P53 prevent tumor invasion and metastasis by down-regulating IDO in lung cancer[J].Oncotarget,2017.[Epub ahead of print]
[36]Heng B,Lim CK,Lovejoy DB,et al.Understanding the role of the kynurenine pathway in human breast cancer immunobiology[J].Oncotarget,2016,7(6):6506-6520.
[37]Asghar K,Farooq A,Zulfiqar B,et al.Indoleamine 2,3-dioxygenase:as a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma[J].World J Gastroenterol,2017,23(13):2286-2293.
[38]Pschowski R,Pape UF,Fusch G,et al.Increased activity of the immunoregulatory enzyme indoleamine-2,3-Dioxygenase with consecutive tryptophan depletion predicts death in patients with neuroendocrine neoplasia[J].Neuroendocrinology,2017,104(2):135-144.
[39]Hudolin T,Mengus C,Coulot J,et al.Expression of indoleamine 2,3-dioxygenase gene is a feature of poorly differentiated non-muscle-invasive urothelial cell bladder carcinomas[J].Anticancer Res,2017,37(3):1375-1380.
[40]Li M,Bolduc AR,Hoda MN,et al.The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma[J].Immunother Cancer,2014,2:21.
[41]Meng X,Du G,Ye L,et al.Combinatorial antitumor effects of indoleamine 2,3-dioxygenase inhibitor NLG919 and paclitaxel in a murine B16-F10 melanoma model[J].Int JImmunopathol Pharmacol,2017,30(3):215-226.
[42]Liu KT,Liu YH,Liu HL,et al.Neutrophils are essential in short hairpin RNA of indoleamine 2,3-dioxygenase mediated-antitumor efficiency[J].Mol Ther Nucleic Acids,2016,5(12):e397.
[43]Holmgaard RB,Zamarin D,Munn DH,et al.Indoleamine2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4[J].Exp Med,2013,210(7):1389-1402.
[44]Gangadhar TC,Hamid O,Smith DC,et al.Preliminary results from a phaseⅠ/Ⅱstudy of epacadostat(incb024360)in combination with pembrolizumab in patients with selected advanced cancers[J].J Immunother Cancer,2015,3(Suppl 2):7.
[45]Bilal Z,Amnah M,Kaenat N,et al.Nanomedicine and cancer immunotherapy:focus on indoleamine 2,3-dioxygenase inhibitors[J].Oncol Targets Ther,2017,10:463-476.
[46]Ogawa K,Hara T,Shimizu M,et al.(-)-Epigallocatechin gallate inhibits the expression of indoleamine 2,3-dioxygenase in human colorectal cancer cells[J].Oncol Lett,2012,4(3):546-550.
[47]Prendergast GC,Smith C,Thomas S,et al.Indoleamine2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer[J].Cancer Immunol Immunother,2014,63(7):721-735.
[48]Soliman HH,Jackson E,Neuger T,et al.A first in man phaseⅠtrial of the oral immunomodulator,indoximod,combined with docetaxel in patients with metastatic solid tumors[J].Oncotarget,2014,5(18):8136-8146.