IDO基因转染小鼠Lewis肺癌细胞诱导Treg细胞增殖的实验研究
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摘要
背景与目的:
目前,肺癌已经成为威胁人类健康最重要的恶性肿瘤之一,非小细胞肺癌(non-small cell lung cancer,NSCLC)占肺癌所有病例的80%以上。尽管以手术、放疗、化疗等为主的治疗方式近年来发展迅速,但由于肺癌患者常发生远处转移,目前肺癌患者的5年生存率只有15%左右。近来研究表明,肺癌的发生、发展及免疫治疗效果不佳均与肺癌细胞的免疫耐受(immune tolerance)密切相关,但至今对免疫耐受发生的机制尚不完全清楚。吲哚胺-2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)是人类机体肝脏以外唯一的色氨酸代谢限速酶,其活性的强弱与免疫T细胞功能之间的关系极为密切。近来研究发现,在人类多种恶性肿瘤局部,该酶表达明显增强,严重影响肿瘤局部的免疫功能,是肿瘤细胞产生免疫逃逸的重要原因,但其作用机制尚不完全清楚。本研究首先观察IDO在NSCLC中的表达和调节性T细胞(Regulatory T cell,Treg)在NSCLC组织和转移淋巴结内的分布,探讨IDO表达与Treg细胞之间可能的相互关系;然后,将IDO基因转染到小鼠Lewis肺癌细胞,观察IDO基因表达对Lewis肺癌细胞生物学行为的影响,再与小鼠外周血T细胞共同培养,体外研究IDO基因表达对Treg细胞的诱导增殖作用以及对Lewis肺癌细胞迁移能力和侵袭能力的调控作用;最后,体内研究IDO基因转染对小鼠Treg细胞的诱导增殖作用及对Lewis肺癌细胞成瘤性、侵袭和转移能力的影响,最后,利用IDO抑制剂1-甲基色氨酸(1-MT)研究对Treg细胞诱导增殖逆转作用,并对其机制进行初步探讨。
方法:
收集在第三军医大学附属新桥医院和西南医院手术治疗的62例患者肺癌组织和瘤周正常肺组织、以及15例肺良性病变组织的新鲜标本和石蜡切片。采用免疫组织化学SP法和荧光半定量RT-PCR方法检测IDO蛋白和mRNA在肺癌组织、瘤周正常肺组织和肺良性病变组织中的表达,并利用免疫组化SP法检测Treg细胞在上述各种组织内的分布情况;之后,采用阳离子脂质体Lipofectmine2000,将含人全长IDO基因的pEGFP-IDO真核表达质粒转染到小鼠Lewis肺癌细胞,G418筛选获得Lewis-IDO细胞,同时设置空白对照组(Lewis细胞)及空质粒转染组(Lewis-EGFP细胞),利用transwell侵袭小室,检测三种细胞在形态学和侵袭力等生物学行为方面的区别;再将Lewis-IDO、Lewis-EGFP和Lewis肺癌细胞分别与小鼠T淋巴细胞混合培养,利用流式细胞技术分析三种细胞对Treg细胞的诱导增殖作用;最后将三种细胞分别种植到C57小鼠,检测小鼠外周血和种植瘤中Treg细胞的增殖、种植瘤和转移灶的形成,1-MT通过加入小鼠饮用水中的方式发挥作用,通过对小鼠种植瘤内IDO基因表达和Treg细胞增殖检测验证对肿瘤局部免疫耐受的调控作用。
结果:
1、肺癌组织、瘤周正常肺组织和肺良性病变组织中IDO表达阳性率分别为67.7% (42/62)、0和13.3% (2/15),前者与后二者比较有显著统计学差异(P <0.01),转移淋巴结内IDO表达阳性率为75.0%(15/20),荧光半定量RT-PCR结果与免疫组化基本一致;肺癌组织、转移淋巴结、瘤周正常肺组织和肺良性病变组织中Treg细胞阳性率分别为83.9%(52/62)、90.0%(18/20)、0和13.3%(2/15),前二者与后二者相互比较有非常显著统计学差异(P <0.01),前二者之间或后二者之间相比较差异无明显统计学意义(P >0.05),IDO阳性表达率与Treg细胞阳性率之间具有非常显著相关性(P <0.01)。
2、IDO基因成功转染到小鼠Lewis肺癌细胞,与Lewis-EGFP细胞和Lewis细胞相比,Lewis-IDO细胞贴壁比例增加,形态变为长梭形,伪足明显增多延长,前二者形态相似;Lewis-IDO细胞侵袭能力增强,破坏matrigel基质蛋白胶层进入下室内的细胞数明显增多,Lewis-IDO、Lewis-EGFP及Lewis细胞分别为237.4±22.1、166.0±14.2和185.6±19.5,前者与后二者比较具有显著统计学意义(P <0.05);Lewis-IDO细胞与小鼠T淋巴细胞共培养后,Treg细胞增殖明显,与Lewis-EGFP细胞(6.2±0.36)%vs(5.0±0.52)%,)及Lewis细胞(6.2±0.36)%vs(4.9±0.4)%相比统计学差异显著(P<0.05)。
3、15只种植Lewis-IDO细胞的小鼠发生肝肺转移的小鼠数量及转移灶为12只和44个转移灶,种植Lewis-EGFP及Lewis细胞的小鼠分别为5只7个转移灶及4只7个转移灶,前者与后二者比较具有显著统计学意义(P=0.01);流式分析结果表明,种植Lewis-IDO细胞的小鼠外周血中Treg细胞比例明显高于Lewis-EGFP细胞组和Lewis细胞组,其比例分别为(13.7±4.5)%、(8.9±3.3)%和(9.2±3.4)%,前者与后二者比较具有显著统计学差异(P <0.05);从平均存活时间来看,种植Lewis-IDO、Lewis-EGFP和Lewis细胞的小鼠平均存活时间分别为(37.1±2.3)天、(45.1±2.6)天和(44.9±2.9)天,前者与后二者比较统计学差异显著(P <0.05),后二者之间无显著统计学差异(P >0.05);
4、采用1-MT干预后,和种植Lewis-IDO细胞的未干预组小鼠比较,干预组IDO表达明显减弱,发生肝肺转移较Lewis-IDO未干预组明显减少,二者相比具有显著统计学意义(P =0.05);干预组小鼠外周血淋巴细胞中Treg细胞比例(9.7±4.0)%与Lewis-IDO未干预组(13.7±4.5)%比较明显减少(P <0.05),干预组小鼠平均存活时间为(42.0±2.3)天,与Lewis-IDO未干预组(37.1±2.3)天相比有增加的趋势,但没有显著统计学意义(P >0.05);
结论:
1、NSCLC组织内IDO基因表达明显增强,同时伴有Treg细胞在NSCLC组织和转移淋巴结内的增殖,且Treg细胞的分布与IDO表达呈正相关,提示IDO基因在NSCLC表达增强可能诱导Treg细胞在肿瘤局部的增殖,从而诱导NSCLC的免疫耐受。
2、IDO基因转染Lewis肺癌细胞可以在体内外诱导Treg细胞增殖,同时可以增强Lewis肺癌细胞的侵袭和转移能力,提示IDO可以作为逆转NSCLC免疫耐受和抑制NSCLC侵袭转移新的治疗靶点。
3、1-MT干预可以明显减少Lewis-IDO细胞的转移及Treg细胞的增殖,但不能完全抑制IDO基因的表达及延长实验小鼠的平均存活时间,故有必要寻找更有效更特异抑制IDO基因表达的方法;
Background and objective:
Metastasis is one of the poor prognostic factors of non-small cell lung cancer(NSCLC). One of the most important causes is immune tolerance within the tumor microenvironment induced by many factors such as regulatory T cell populations,inhibitory ligands such as PD-L1,soluble factors such as TGFb,and the activity of nutrient-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO). Increasing evidences are accumulating to indicate that IDO and regulatory T cell(Treg) play an important role in the induction of immune tolerance in tumor microenvironment.However the relationship between the expression of IDO and the distribution of Tregs in NSCLC has not been completely elucidated. The present study aimed to investigate the IDO expression in NSCLC and the distribution of Tregs in NSCLC tissues and the metastastic lymph nodes,and the potential relationships between them.Besides that,we investigate the effects of mouse Lewis lung cancer cell line transfected with IDO gene on the induction of the proliferation of Treg cell in vitro and in vivo and the effects of IDO(+) lung cancer cell on the invasion and metastasis of mouse Lewis lung cancer cell,thereby exploring its possible mechanisms.1-Methyl tryptophan(1-MT), the IDO competitive inhibitor, was tried to reverse the proliferation of Treg cell.
Methods:
Sixty two patients with NSCLC and fifteen patients with benign lung disease from Xinqiao hospital and Southwest hospital were involved in the present study. The IDO expression in lung cancer, the peritumorous normal lung tissues and the benign control tissues was detected by streptavidin-peroxidase(SP) immunohistochemistry (IHC) and fluorescent semi-quantitative RT-PCR. The distribution of Treg cell was detected by SP IHC as well. With the use of the cationic liposome Lipofectamine 2000,the eukaryotic expression plasmid vectors pEGFP-N1 carrying human IDO cDNA was transfected into mouse Lewis lung cancer cell line(named Lewis-IDO) and then co-cultured with T lymphocytes from the peripheral blood of C57 mouse.The parental Lewis cells and Lewis cells transfected with blank plasmid pEGFP-N1(named Lewis-EGFP) was used as control groups.After co-culture,the Treg cells were sorted using fluorescence-activated cell sorting (FACS). The capability of invasion and metastasis in vitro was studied by using of transwell experiment. To evaluate the tumorgenicity and metastastic ability of IDO gene on cancer cell,the Lewis-IDO, Lewis-EGFP and Lewis cells were transplanted in C57 mouse respectively. The Tregs in the peripheral blood(PB) and cancer mass were detected by FACS. 1-MT was used in the drinking water of mouse with a concentration of 5mg/ml.
Results:
1. The positive IDO expression rates in lung cancer cell, corresponding normal lung tissues and benign disease tissues were 67.7% (42/62)、0 and 13.3% (2/15) , respectively.There were significant differences between cancer mass and benign disease tissues, peritumorous normal lung tissues(P<0.01).The positive IDO expression rate in metastastic lymph node was 75.0%(15/20). The results of fluorescent semi-quantitative RT-PCR were consistent with the results of IHC. The percentage of Treg cells in lung cancer tissues, metastastic lymph node, peritumorous normal lung tissues and benign disease tissues were 83.9%(52/62)、90.0%(18/20)、0 and 13.3%(2/15), respectively. Significant differences were also seen between the former two and the latter two(P <0.01),but there was no significant differences between the two formers or the two latters(P >0.05). The spearman rank correlation analysis revealed the distribution of Treg cells is correlated with the expression of IDO(R=0.448,P <0.01).
2. The IDO gene was transfected into Lewis cell successfully. Compared with the Lewis-EGFP and Lewis cells,Lewis-IDO cells became longer and had more filopodia.By transwell chamber system,the invasion capability of Lewis-IDO cells was significantly increased. The quantity of the Lewis-IDO cells breaking through the matrigel increased significantly(P<0.05). The Lewis-IDO cells could induce the proliferation of Treg cells.There was significant differences between the Lewis-IDO cells and Lewis-EGFP cells(6.2±0.36% vs 5.0±0.52%,P<0.05) and between the Lewis-IDO cells and Lewis cells(6.2±1.6% vs 4.9±0.4%,P<0.05).
3. The time of tumor formation was different among the three groups but there were no significant differences.The capability of metastasis to lung and liver of Lewis-IDO cell was significantly higher than that of Lewis-EGFP cells or Lewis cells(P =0.01) The Treg cells in PB of the mouse transplanted with Lewis-IDO cells were statistically higher than that from the mouse transplanted with Lewis-EGFP cells or Lewis cells(P <0.05),the values are (13.7±4.5)%, (8.9±3.3)% and (9.2±3.4)% respectively.The mean survival time of Lewis-IDO(37.1±2.3 days) group was significantly longer than Lewis-EGFP group(45.1±2.6 days) or Lewis group(44.9±2.9 days) (P <0.05).
4. After the treatment with 1-MT, the IDO expression was inhibited by IHC.The proliferation of Treg cell was significantly reduced than untreated group( (9.7±4.0) % vs (13.7±4.5)%,P <0.05). The metastasis to lung and liver was significantly reduced than untreated Lewis-IDO group(P <0.05).The mean survival time(42.0±2.3 days) of C57 mouse was longer than that of Lewis-IDO group(37.1±2.3 days) but there was no significant difference(P >0.05).
Conclusions:
1. The overexpression of IDO is a common molecular abnormality both in lung cancer and in metastasic lymph node and is associated with the proliferation of Treg cell in tumor microenvironment of NSCLC.It implicates that the IDO(+) cancer cell might be concerned with the tumor immune tolerance by inducing the proliferation of Treg cells in tumor microenvironment and suggests that strategies to regulate the IDO activity may be beneficial in the immunotherapy of human NSCLC.
2. The tranfection of IDO gene into Lewis lung cancinoma cell can induce the proliferation of Treg cells and increase the Lewis cell’s capability of invasion and metastasis both in vitro and in vivo which implicate that IDO is a new treatment target for reverse the immune tolerance of NSCLC and inhibit the invasion and metastasis of NSCLC.
3. 1-MT treatment can significantly reduce the metastasis of NSCLC and the proliferation of Treg, but can not completely inhibits the IDO expression and significantly prolong the mean survival time of mouse.It is necessary to investigate more effective and specific methods to inbibit IDO-mediated immune tolerance..
目前,肺癌已经成为威胁人类健康最重要的恶性肿瘤之一,非小细胞肺癌(non-small cell lung cancer,NSCLC)占肺癌所有病例的80%以上。尽管以手术、放疗、化疗等为主的治疗方式近年来发展迅速,但由于肺癌患者常发生远处转移,目前肺癌患者的5年生存率只有15%左右。近来研究表明,肺癌的发生、发展及免疫治疗效果不佳均与肺癌细胞的免疫耐受(immune tolerance)密切相关,但至今对免疫耐受发生的机制尚不完全清楚。吲哚胺-2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)是人类机体肝脏以外唯一的色氨酸代谢限速酶,其活性的强弱与免疫T细胞功能之间的关系极为密切。近来研究发现,在人类多种恶性肿瘤局部,该酶表达明显增强,严重影响肿瘤局部的免疫功能,是肿瘤细胞产生免疫逃逸的重要原因,但其作用机制尚不完全清楚。本研究首先观察IDO在NSCLC中的表达和调节性T细胞(Regulatory T cell,Treg)在NSCLC组织和转移淋巴结内的分布,探讨IDO表达与Treg细胞之间可能的相互关系;然后,将IDO基因转染到小鼠Lewis肺癌细胞,观察IDO基因表达对Lewis肺癌细胞生物学行为的影响,再与小鼠外周血T细胞共同培养,体外研究IDO基因表达对Treg细胞的诱导增殖作用以及对Lewis肺癌细胞迁移能力和侵袭能力的调控作用;最后,体内研究IDO基因转染对小鼠Treg细胞的诱导增殖作用及对Lewis肺癌细胞成瘤性、侵袭和转移能力的影响,最后,利用IDO抑制剂1-甲基色氨酸(1-MT)研究对Treg细胞诱导增殖逆转作用,并对其机制进行初步探讨。
方法:
收集在第三军医大学附属新桥医院和西南医院手术治疗的62例患者肺癌组织和瘤周正常肺组织、以及15例肺良性病变组织的新鲜标本和石蜡切片。采用免疫组织化学SP法和荧光半定量RT-PCR方法检测IDO蛋白和mRNA在肺癌组织、瘤周正常肺组织和肺良性病变组织中的表达,并利用免疫组化SP法检测Treg细胞在上述各种组织内的分布情况;之后,采用阳离子脂质体Lipofectmine2000,将含人全长IDO基因的pEGFP-IDO真核表达质粒转染到小鼠Lewis肺癌细胞,G418筛选获得Lewis-IDO细胞,同时设置空白对照组(Lewis细胞)及空质粒转染组(Lewis-EGFP细胞),利用transwell侵袭小室,检测三种细胞在形态学和侵袭力等生物学行为方面的区别;再将Lewis-IDO、Lewis-EGFP和Lewis肺癌细胞分别与小鼠T淋巴细胞混合培养,利用流式细胞技术分析三种细胞对Treg细胞的诱导增殖作用;最后将三种细胞分别种植到C57小鼠,检测小鼠外周血和种植瘤中Treg细胞的增殖、种植瘤和转移灶的形成,1-MT通过加入小鼠饮用水中的方式发挥作用,通过对小鼠种植瘤内IDO基因表达和Treg细胞增殖检测验证对肿瘤局部免疫耐受的调控作用。
结果:
1、肺癌组织、瘤周正常肺组织和肺良性病变组织中IDO表达阳性率分别为67.7% (42/62)、0和13.3% (2/15),前者与后二者比较有显著统计学差异(P <0.01),转移淋巴结内IDO表达阳性率为75.0%(15/20),荧光半定量RT-PCR结果与免疫组化基本一致;肺癌组织、转移淋巴结、瘤周正常肺组织和肺良性病变组织中Treg细胞阳性率分别为83.9%(52/62)、90.0%(18/20)、0和13.3%(2/15),前二者与后二者相互比较有非常显著统计学差异(P <0.01),前二者之间或后二者之间相比较差异无明显统计学意义(P >0.05),IDO阳性表达率与Treg细胞阳性率之间具有非常显著相关性(P <0.01)。
2、IDO基因成功转染到小鼠Lewis肺癌细胞,与Lewis-EGFP细胞和Lewis细胞相比,Lewis-IDO细胞贴壁比例增加,形态变为长梭形,伪足明显增多延长,前二者形态相似;Lewis-IDO细胞侵袭能力增强,破坏matrigel基质蛋白胶层进入下室内的细胞数明显增多,Lewis-IDO、Lewis-EGFP及Lewis细胞分别为237.4±22.1、166.0±14.2和185.6±19.5,前者与后二者比较具有显著统计学意义(P <0.05);Lewis-IDO细胞与小鼠T淋巴细胞共培养后,Treg细胞增殖明显,与Lewis-EGFP细胞(6.2±0.36)%vs(5.0±0.52)%,)及Lewis细胞(6.2±0.36)%vs(4.9±0.4)%相比统计学差异显著(P<0.05)。
3、15只种植Lewis-IDO细胞的小鼠发生肝肺转移的小鼠数量及转移灶为12只和44个转移灶,种植Lewis-EGFP及Lewis细胞的小鼠分别为5只7个转移灶及4只7个转移灶,前者与后二者比较具有显著统计学意义(P=0.01);流式分析结果表明,种植Lewis-IDO细胞的小鼠外周血中Treg细胞比例明显高于Lewis-EGFP细胞组和Lewis细胞组,其比例分别为(13.7±4.5)%、(8.9±3.3)%和(9.2±3.4)%,前者与后二者比较具有显著统计学差异(P <0.05);从平均存活时间来看,种植Lewis-IDO、Lewis-EGFP和Lewis细胞的小鼠平均存活时间分别为(37.1±2.3)天、(45.1±2.6)天和(44.9±2.9)天,前者与后二者比较统计学差异显著(P <0.05),后二者之间无显著统计学差异(P >0.05);
4、采用1-MT干预后,和种植Lewis-IDO细胞的未干预组小鼠比较,干预组IDO表达明显减弱,发生肝肺转移较Lewis-IDO未干预组明显减少,二者相比具有显著统计学意义(P =0.05);干预组小鼠外周血淋巴细胞中Treg细胞比例(9.7±4.0)%与Lewis-IDO未干预组(13.7±4.5)%比较明显减少(P <0.05),干预组小鼠平均存活时间为(42.0±2.3)天,与Lewis-IDO未干预组(37.1±2.3)天相比有增加的趋势,但没有显著统计学意义(P >0.05);
结论:
1、NSCLC组织内IDO基因表达明显增强,同时伴有Treg细胞在NSCLC组织和转移淋巴结内的增殖,且Treg细胞的分布与IDO表达呈正相关,提示IDO基因在NSCLC表达增强可能诱导Treg细胞在肿瘤局部的增殖,从而诱导NSCLC的免疫耐受。
2、IDO基因转染Lewis肺癌细胞可以在体内外诱导Treg细胞增殖,同时可以增强Lewis肺癌细胞的侵袭和转移能力,提示IDO可以作为逆转NSCLC免疫耐受和抑制NSCLC侵袭转移新的治疗靶点。
3、1-MT干预可以明显减少Lewis-IDO细胞的转移及Treg细胞的增殖,但不能完全抑制IDO基因的表达及延长实验小鼠的平均存活时间,故有必要寻找更有效更特异抑制IDO基因表达的方法;
Background and objective:
Metastasis is one of the poor prognostic factors of non-small cell lung cancer(NSCLC). One of the most important causes is immune tolerance within the tumor microenvironment induced by many factors such as regulatory T cell populations,inhibitory ligands such as PD-L1,soluble factors such as TGFb,and the activity of nutrient-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO). Increasing evidences are accumulating to indicate that IDO and regulatory T cell(Treg) play an important role in the induction of immune tolerance in tumor microenvironment.However the relationship between the expression of IDO and the distribution of Tregs in NSCLC has not been completely elucidated. The present study aimed to investigate the IDO expression in NSCLC and the distribution of Tregs in NSCLC tissues and the metastastic lymph nodes,and the potential relationships between them.Besides that,we investigate the effects of mouse Lewis lung cancer cell line transfected with IDO gene on the induction of the proliferation of Treg cell in vitro and in vivo and the effects of IDO(+) lung cancer cell on the invasion and metastasis of mouse Lewis lung cancer cell,thereby exploring its possible mechanisms.1-Methyl tryptophan(1-MT), the IDO competitive inhibitor, was tried to reverse the proliferation of Treg cell.
Methods:
Sixty two patients with NSCLC and fifteen patients with benign lung disease from Xinqiao hospital and Southwest hospital were involved in the present study. The IDO expression in lung cancer, the peritumorous normal lung tissues and the benign control tissues was detected by streptavidin-peroxidase(SP) immunohistochemistry (IHC) and fluorescent semi-quantitative RT-PCR. The distribution of Treg cell was detected by SP IHC as well. With the use of the cationic liposome Lipofectamine 2000,the eukaryotic expression plasmid vectors pEGFP-N1 carrying human IDO cDNA was transfected into mouse Lewis lung cancer cell line(named Lewis-IDO) and then co-cultured with T lymphocytes from the peripheral blood of C57 mouse.The parental Lewis cells and Lewis cells transfected with blank plasmid pEGFP-N1(named Lewis-EGFP) was used as control groups.After co-culture,the Treg cells were sorted using fluorescence-activated cell sorting (FACS). The capability of invasion and metastasis in vitro was studied by using of transwell experiment. To evaluate the tumorgenicity and metastastic ability of IDO gene on cancer cell,the Lewis-IDO, Lewis-EGFP and Lewis cells were transplanted in C57 mouse respectively. The Tregs in the peripheral blood(PB) and cancer mass were detected by FACS. 1-MT was used in the drinking water of mouse with a concentration of 5mg/ml.
Results:
1. The positive IDO expression rates in lung cancer cell, corresponding normal lung tissues and benign disease tissues were 67.7% (42/62)、0 and 13.3% (2/15) , respectively.There were significant differences between cancer mass and benign disease tissues, peritumorous normal lung tissues(P<0.01).The positive IDO expression rate in metastastic lymph node was 75.0%(15/20). The results of fluorescent semi-quantitative RT-PCR were consistent with the results of IHC. The percentage of Treg cells in lung cancer tissues, metastastic lymph node, peritumorous normal lung tissues and benign disease tissues were 83.9%(52/62)、90.0%(18/20)、0 and 13.3%(2/15), respectively. Significant differences were also seen between the former two and the latter two(P <0.01),but there was no significant differences between the two formers or the two latters(P >0.05). The spearman rank correlation analysis revealed the distribution of Treg cells is correlated with the expression of IDO(R=0.448,P <0.01).
2. The IDO gene was transfected into Lewis cell successfully. Compared with the Lewis-EGFP and Lewis cells,Lewis-IDO cells became longer and had more filopodia.By transwell chamber system,the invasion capability of Lewis-IDO cells was significantly increased. The quantity of the Lewis-IDO cells breaking through the matrigel increased significantly(P<0.05). The Lewis-IDO cells could induce the proliferation of Treg cells.There was significant differences between the Lewis-IDO cells and Lewis-EGFP cells(6.2±0.36% vs 5.0±0.52%,P<0.05) and between the Lewis-IDO cells and Lewis cells(6.2±1.6% vs 4.9±0.4%,P<0.05).
3. The time of tumor formation was different among the three groups but there were no significant differences.The capability of metastasis to lung and liver of Lewis-IDO cell was significantly higher than that of Lewis-EGFP cells or Lewis cells(P =0.01) The Treg cells in PB of the mouse transplanted with Lewis-IDO cells were statistically higher than that from the mouse transplanted with Lewis-EGFP cells or Lewis cells(P <0.05),the values are (13.7±4.5)%, (8.9±3.3)% and (9.2±3.4)% respectively.The mean survival time of Lewis-IDO(37.1±2.3 days) group was significantly longer than Lewis-EGFP group(45.1±2.6 days) or Lewis group(44.9±2.9 days) (P <0.05).
4. After the treatment with 1-MT, the IDO expression was inhibited by IHC.The proliferation of Treg cell was significantly reduced than untreated group( (9.7±4.0) % vs (13.7±4.5)%,P <0.05). The metastasis to lung and liver was significantly reduced than untreated Lewis-IDO group(P <0.05).The mean survival time(42.0±2.3 days) of C57 mouse was longer than that of Lewis-IDO group(37.1±2.3 days) but there was no significant difference(P >0.05).
Conclusions:
1. The overexpression of IDO is a common molecular abnormality both in lung cancer and in metastasic lymph node and is associated with the proliferation of Treg cell in tumor microenvironment of NSCLC.It implicates that the IDO(+) cancer cell might be concerned with the tumor immune tolerance by inducing the proliferation of Treg cells in tumor microenvironment and suggests that strategies to regulate the IDO activity may be beneficial in the immunotherapy of human NSCLC.
2. The tranfection of IDO gene into Lewis lung cancinoma cell can induce the proliferation of Treg cells and increase the Lewis cell’s capability of invasion and metastasis both in vitro and in vivo which implicate that IDO is a new treatment target for reverse the immune tolerance of NSCLC and inhibit the invasion and metastasis of NSCLC.
3. 1-MT treatment can significantly reduce the metastasis of NSCLC and the proliferation of Treg, but can not completely inhibits the IDO expression and significantly prolong the mean survival time of mouse.It is necessary to investigate more effective and specific methods to inbibit IDO-mediated immune tolerance..
引文
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