Brief Article
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World J Gastroenterol. Mar 7, 2012; 18(9): 971-978
Published online Mar 7, 2012. doi: 10.3748/wjg.v18.i9.971
B7-H1 expression is associated with expansion of regulatory T cells in colorectal carcinoma
Dong Hua, Jing Sun, Yong Mao, Lu-Jun Chen, Yu-Yu Wu, Xue-Guang Zhang
Dong Hua, Yong Mao, Department of Oncology, the Fourth Affiliated Hospital of Suzhou University, Wuxi 214062, Jiangsu Province, China
Yu-Yu Wu, Department of Pathology, The Fourth Affiliated Hospital of Soochow University, Wuxi 214062, Jiangsu Province, China
Jing Sun, Yong Mao, Xue-Guang Zhang, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, Jiangsu Province, China
Lu-Jun Chen, Clinical central Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu Province, China
Author contributions: Hua D and Sun J contributed equally to this work; Hua D and Sun J designed the research; Mao Y, Chen LJ and Wu YY performed the research; Sun J and Chen LJ analyzed data; and Hua D and Jing Sun wrote the paper; Zhang XG supervised the experiment design and revised the manuscript.
Supported by Grants from the Major State Basic Research Development Program of China 973 Program, No. 2007CB512402; National Natural Science Foundation of China, No. 31100634; Natural Science Foundation of Jiangsu Province, No. BK2010161; and “333” Project of Wuxi City, Jiangsu Province, No. CAE00901-09
Correspondence to: Xue-Guang Zhang, Professor, Institute of Medical Biotechnology, Medical College of Soochow University, 708 Renmin Road, Suzhou 215007, Jiangsu Province, China. xueguangzh@yahoo.com.cn
Telephone: +86-512-65104908 Fax: +86-512-65104908
Received: May 12, 2011
Revised: November 17, 2011
Accepted: December 31, 2011
Published online: March 7, 2012
Abstract

AIM: To investigate the expression of B7-H1 in human colorectal carcinoma (CRC) to define its regulating effects on T cells in tumor microenvironment.

METHODS: One hundred and two paraffin blocks and 33 fresh samples of CRC tissues were subject to this study. Immunohistochemistry was performed for B7-H1 and CD3 staining in CRC tissues. Ficoll-Hypaque density gradient centrifugation was used to isolate peripheral blood mononuclear cells of fresh CRC tissues; flow cytometry and immunofluorescence staining were used for detection of regulatory T cells. Data was analyzed with statistical software.

RESULTS: Costimulatory molecule B7-H1 was found strongly expressed in CRC tissues, localized in tumor cell membrane and cytoplasm, while weak or none expression of B7-H1 was detected in pared normal colorectal tissues. Meanwhile, CD3 positive T cells were found congregated in CRC tumor nest and stroma. Statistic analysis showed that B7-H1 expression level was negatively correlated to the total T cell density in tumor nest (P < 0.0001) and tumor stroma (P = 0.0200) of 102 cases of CRC tissues. Among the total T cells, a variable amount of regulatory T cells with a clear Foxp3+ (forkhead box P3) staining could be detected in CRC tissues and patients’ blood. Interestingly, in the 33 samples (15 cases of B7-H1high CRC tissues and 18 cases of B7-H1low CRC tissues) of freshly isolated mononuclear cells from CRC tissues, the percentages of CD4+Foxp3+ and CD8+Foxp3+ regulatory T cells were found remarkably higher in B7-H1high CRC tissues than in B7-H1low CRC tissues (P = 0.0024, P = 0.0182), indicating that B7-H1 expression was involved in proliferation of regulatory T cell. No significant difference was found in CRC peripheral blood (P = 0.0863, P = 0.0678). PD-1 is the specific ligand for B7-H1 pathway transferring inhibitory signal to T cell, which is expressed by activated T cell. Our further analysis of PD-1 expression on T cells in CRC tissues showed that conventional T cells (CD4+Foxp3-/CD8+Foxp3-), which was thought to contribute to the anti-tumor immune response, highly expressed PD-1; while regulatory T cells (CD4+Foxp3+/CD8+Foxp3-) almost failed to express PD-1. The average percentage of PD-1 expression on regulatory T cells was significantly higher than the percentage of PD-1 on conventional T cells (CD4+Foxp3- T cell, P < 0.0001; CD8+Foxp3- T cell, P < 0.0001). The diverse expression of PD-1 might lead to different fate of T cell subsets in B7-H1 over-expression CRC tumor microenvironment.

CONCLUSION: B7-H1 expression in tumor cells can inhibit the conventional T cell proliferation in tumor microenvironment through the PD-1 expression on conventional T cells.

Keywords: Costimulatory molecule, B7-H1, PD-1, Regulatory T cell, Colorectal carcinoma