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

doi:10.13481/j.1671-587x.20180316

摘要/Abstract

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（χ²=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（χ²=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。

关键词: 调节性T细胞, B7-H4, B7-H1, 结直肠肿瘤

Abstract: 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) infiltrationin 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(χ²=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(χ²=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.

Key words: regulatory T cells, colorectal neoplasms, B7-H1, B7-H4

中图分类号:

R735.35

王丹, 李怡飞, 历春, 董志恒, 董营, 盖晓东. 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[J]. 吉林大学学报(医学版), 2018, 44(03): 543-547.

WANG Dan, LI Yifei, LI Chun, DONG Zhiheng, DONG Ying, GAI Xiaodong. Relationships between expressions of B7-H1 and B7-H4 and Foxp3⁺ regulated T-cell infiltration in colorectal cancer tissue[J]. Journal of Jilin University Medicine Edition, 2018, 44(03): 543-547.

参考文献

[1] Koudougou C,Bonneville M,Matysiak-Budnik T,et al. Review article:antitumoural immunity in colorectal cancer-current and potential future implications in clinical practice[J].Aliment Pharmacol Ther,2013,38(1):3-15.
[2] Ichikawa M,Chen L.Role of B7-H1 and B7-H4 molecules 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-H1 expression 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-H3 and B7x are 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-β of lung cancer microenvironment upregulates B7H1 and 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-H4 as a novel prognostic marker in breast cancer[J].Gene,2017,623:24-28.
[11] Park JJ, Omiya R,Matsumura Y,et al.B7-H1/CD80 interaction 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-H1andB7-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-H1 and B7-H4 in ovarian cancer[J].Oncol Lett,2015,11(4):2815-2819.
[15] Wang X,Hao J,Metzger DL,et al.B7-H4 treatment 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-H4 for hepatocellular carcinoma[J].J Surg Res,2015,197 (2):301-306.
[18] Groeger S,Jarzina F,Mamat U,et al.Induction of B7-H1 receptor 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.Site-specific 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.