结直肠癌组织中B7-H1和B7-H4表达与Foxp3~+调节性T细胞浸润的关联性
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摘要
目的:探讨B7-H1和B7-H4在结直肠癌(CRC)组织中的表达及其与肿瘤中Foxp3~+调节性T细胞(Treg)浸润的关系,为判定CRC的生物学行为及预后提供依据。方法:免疫组织化学法检测56例CRC患者肿瘤标本及癌旁正常组织样本中B7-H1、B7-H4蛋白的表达和Treg的浸润情况,并与CRC患者的临床病理特征进行关联性分析。结果:CRC患者CRC组织中B7-H1阳性表达率高于癌旁正常组织(χ~2=72.34,P<0.01)。不同浸润深度的CRC组织中B7-H1表达频数比较差异有统计学意义(P<0.01);淋巴结转移阳性者CRC组织中B7-H1高表达频数高于淋巴结转移阴性者(P<0.01);Duke’s分期C+D者CRC组织中B7-H1高表达频数高于Duke’s分期A+B者(P<0.01)。CRC组织中B7-H4阳性表达率高于癌旁正常组织(χ~2=78.92,P<0.01)。不同浸润深度的CRC组织中B7-H4高表达频数比较差异有统计学意义(P<0.05),淋巴结转移阳性者CRC组织中B7-H4高表达频数高于淋巴结转移阴性者(P<0.05);肿瘤组织中Treg阳性细胞数明显高于癌旁正常组织(P<0.01);分化程度不同CRC组织中Treg阳性细胞数比较差异有统计学意义(P<0.01);淋巴结转移阳性者CRC组织中Treg阳性细胞数高于淋巴结转移阴性者(P<0.01)。Treg浸润与B7-H1的表达有相关性(P<0.01,Cramer’s=0.463),Treg浸润与B7-H4的表达有相关性(P<0.05,Cramer’s=0.320)。结论:B7-H1和B7-H4在CRC组织中呈异常高表达,并与肿瘤中Treg浸润增加有关,可作为评估CRC预后的指标。
Objective:To explore the expressions of B7-H1 and B7-H4 in colorectal cancer(CRC)tissue and their relationships with the Foxp3~+ regulated T-cell(Treg)infiltration in tumor tissue,and to provide the basis for judging the biological behaviours and prognosis of CRC.Methods:Immunohistochemistry was used to detect the expressions of B7-H1 and B7-H4 and the infiltration of Treg in 56 cases of CRC tissue samples and adjacent normal tissue samples,and their relationships with the clinicopathological features of CRC patients were analyzed.Results:The positive expression rate of B7-H1 in CRC tissue of the CRC patients was higher than that in adjacent normal tissue(χ~2=72.34,P<0.01).The differences of expression frequencies of B7-H1 in CRC tissues with different infiltration depths were significant(P<0.01).The high expression frequency of B7-H1 in CRC tissue of the patients with positive lymphnode metastasis was higher than that in the patients with negative lymphnode metastasis(P<0.01).The high expression frequency of B7-H1 in CRC tissue of the patients at Duke's stage(C+D)was higher than that of the patients at Duke's stage(A+B)(P<0.01).The positive expression rate of B7-H4 in CRC tissue was higher than that in adjacent normal tissue(χ~2=78.92,P<0.01).The differences of expression frequencies of B7-H4 in CRC tissues with different infiltration depths were significant(P<0.05).The high expression frequency of B7-H4 in CRC tissue of the patients with positive lymphnode metastasis was higher than that of the patients with negative lymphnode metastasis(P<0.05).The number of Treg positive expression cells in CRC tissue was significantly higher than that in adjacent normal tissue(P<0.01),the number of Treg postive expression cells in CRC tissues with different differentiation degrees were different(P<0.01),and the number of Treg positive expression cells in CRC tissue of the patients with positive lymphnode metastasis was higher than that of the patients with negative lymph node metastasis(P<0.01).The expression of B7-H1 was correlated with Treg infiltration(P <0.01,Cramer's=0.463);the expression of B7-H4 was correlated with Treg infiltration(P<0.05,Cramer's=0.320).Conclusion:B7-H1 and B7-H4 are highly expressed in human CRC tissue,and they are associated with the increasing of Treg infiltration;they can be used as the indicators to judge the prognosis of CRC.
Objective:To explore the expressions of B7-H1 and B7-H4 in colorectal cancer(CRC)tissue and their relationships with the Foxp3~+ regulated T-cell(Treg)infiltration in tumor tissue,and to provide the basis for judging the biological behaviours and prognosis of CRC.Methods:Immunohistochemistry was used to detect the expressions of B7-H1 and B7-H4 and the infiltration of Treg in 56 cases of CRC tissue samples and adjacent normal tissue samples,and their relationships with the clinicopathological features of CRC patients were analyzed.Results:The positive expression rate of B7-H1 in CRC tissue of the CRC patients was higher than that in adjacent normal tissue(χ~2=72.34,P<0.01).The differences of expression frequencies of B7-H1 in CRC tissues with different infiltration depths were significant(P<0.01).The high expression frequency of B7-H1 in CRC tissue of the patients with positive lymphnode metastasis was higher than that in the patients with negative lymphnode metastasis(P<0.01).The high expression frequency of B7-H1 in CRC tissue of the patients at Duke's stage(C+D)was higher than that of the patients at Duke's stage(A+B)(P<0.01).The positive expression rate of B7-H4 in CRC tissue was higher than that in adjacent normal tissue(χ~2=78.92,P<0.01).The differences of expression frequencies of B7-H4 in CRC tissues with different infiltration depths were significant(P<0.05).The high expression frequency of B7-H4 in CRC tissue of the patients with positive lymphnode metastasis was higher than that of the patients with negative lymphnode metastasis(P<0.05).The number of Treg positive expression cells in CRC tissue was significantly higher than that in adjacent normal tissue(P<0.01),the number of Treg postive expression cells in CRC tissues with different differentiation degrees were different(P<0.01),and the number of Treg positive expression cells in CRC tissue of the patients with positive lymphnode metastasis was higher than that of the patients with negative lymph node metastasis(P<0.01).The expression of B7-H1 was correlated with Treg infiltration(P <0.01,Cramer's=0.463);the expression of B7-H4 was correlated with Treg infiltration(P<0.05,Cramer's=0.320).Conclusion:B7-H1 and B7-H4 are highly expressed in human CRC tissue,and they are associated with the increasing of Treg infiltration;they can be used as the indicators to judge the prognosis of CRC.
引文
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[2]Ichikawa M,Chen L.Role of B7-H1and B7-H4molecules in down-regulating effector phase of T-cell immunity:novel cancer escaping mechanisms[J].Front Biosci,2005,10:2856-2860.
[3]Mirza N,Duque MA,Dominguez AL,et al.B7-H1expression on old CD8+T cells negatively regulates the activation of immune responses in aged animals[J].J Immunol,2010,184(10):5466-5474.
[4]Zang X,Thompson RH,Al-Ahmadie HA,et al.B7-H3and B7xare highly expressed in human prostate cancer and associated with disease spread and poor outcome[J].Proc Natl Acad Sci USA,2007,104(49):19458-19463.
[5]Janakiram M,Abadi YM,Sparano JA,et al.T cell coinhibition and immunotherapy in human breast cancer[J].Discov Med,2012,14(77):229-236.
[6]Hori S,Nomura T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3[J].Science,2003,299(5609):1057-1061.
[7]Nomura T,Sakaguchi S.Naturally arising CD4+CD25+regulartory T cells in tumor immunity[J].Curr Top Microbiol Immunol,2005,293:287-302.
[8]Ni XY,Sui HX,Liu Y,et al.TGF-βof lung cancer microenvironment upregulates B7H1and GITRL expression in dendritic cells and is associated with regulatory T cell generation[J].Oncol Rep,2012,28(2):615-621.
[9]Kristensen NN,Schmidt EG,Rasmussen S,et al.B7-H4-Ig treatment of normal mice changes lymphocyte homeostasis and increases the potential of regulatory T cells[J].Immunopharmacol Immunotoxicol,2013,35(4):505-513.
[10]Huang H,Li C,Ren G.Clinical significance of the B7-H4as a novel prognostic marker in breast cancer[J].Gene,2017,623:24-28.
[11]Park JJ,Omiya R,Matsumura Y,et al.B7-H1/CD80interaction is required for the induction and maintenance of peripheral T-cell tolerance[J].Blood,2010,116(8):1291-1298.
[12]Akimova T,Levine MH,Beier UH,et al.Standardization,evaluation,and area-under-curve analysis of human and murine Treg suppressive function[J].Methods Mol Biol,2016,1371(1):43-78.
[13]Zhao LW,Li C,Zhang RL,et al.B7-H1 and B7-H4expression in colorectal carcinoma:correlation with tumor Foxp3+regulatory T-cell infiltration[J].Acta Histochem,2014,116(7):1163-1168.
[14]Xu M,Zhang B,Zhang M,et al.Clinical relevance of expression of B7-H1and B7-H4in ovarian cancer[J].Oncol Lett,2015,11(4):2815-2819.
[15]Wang X,Hao J,Metzger DL,et al.B7-H4treatment of T cells inhibits ERK,JNK,p38,and AKT activation[J].PLoS One,2012,7(1):e28232.
[16]Parsa AT,Bloch O,Crane C,et al.Gliomas promote induction of b7-h1/pd-l1 expression on monocytes:clinical evidence of an immunosuppressive mechanism that can be targeted with antibody blockade[J].Neuro Oncol,2014,16:iii41.
[17]Zhang C,Li Y,Wang Y.Diagnostic value of serum B7-H4for hepatocellular carcinoma[J].J Surg Res,2015,197(2):301-306.
[18]Groeger S,Jarzina F,Mamat U,et al.Induction of B7-H1receptor by bacterial cells fractions of Porphyromonas gingivalis on human oral epithelial cells[J].Immunobiology,2017,222(2):137-147.
[19]Hirunwidchayarat W,Furusawa E,Kang S,et al.Sitespecific regulation of oral mucosa-recruiting CD8+T cells in a mouse contact allergy model[J].Biochem Biophys Res Commun,2017,490(4):1294-1300.
[20]Zou W,Chen L.Inhibitory B7-family molecules in the tumour microenvironment[J].Nat Rev Immunol,2008,8(6):467-477.