Brief Article
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Apr 21, 2011; 17(15): 2019-2027
Published online Apr 21, 2011. doi: 10.3748/wjg.v17.i15.2019
Gastric cancer cells induce human CD4+Foxp3+ regulatory T cells through the production of TGF-β1
Xiang-Liang Yuan, Lei Chen, Tong-Tong Zhang, Yan-Hui Ma, Yun-Lan Zhou, Yan Zhao, Wei-Wei Wang, Ping Dong, Liang Yu, Yan-Yun Zhang, Li-Song Shen
Xiang-Liang Yuan, Tong-Tong Zhang, Yan-Hui Ma, Yun-Lan Zhou, Yan Zhao, Wei-Wei Wang, Li-Song Shen, Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Lei Chen, Ping Dong, Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Xiang-Liang Yuan, Yan-Yun Zhang, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and SJTUSM, Shanghai 200025, China
Liang Yu, Center for Cancer Research, Monash Institute for Medical Research, Monash University, Melbourne, VIC 3168, Australia
Author contributions: Yuan XL, Chen L, Shen LS and Zhang YY contributed equally to this work; Shen LS and Zhang YY designed research; Yuan XL, Chen L, Zhang TT, Ma YH, Zhou YL and Zhao Y performed research; Yuan XL, Chen L, Wang WW, Dong P and Yu L analyzed the data; Yuan XL, Shen LS and Zhang YY wrote the paper.
Supported by Shanghai Municipal Natural Science Foundation, No. 10ZR1420000 and National Natural Science Foundation of China, No. 81072009
Correspondence to: Li-Song Shen, MD, PhD, Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. lisongshen@hotmail.com
Telephone: +86-21-25077070 Fax: +86-21-27075173
Received: December 19, 2010
Revised: December 28, 2010
Accepted: January 4, 2011
Published online: April 21, 2011
Abstract

AIM: To elucidate the molecular and cellular features responsible for the increase of regulatory T cells (Tregs) in gastric cancer.

METHODS: The frequencies of CD4+Foxp3+ Tregs and the level of transforming growth factor-β1 (TGF-β1) were analyzed from 56 patients with gastric cancer by flow cytometry and enzyme-linked immunosorbent assay respectively. Foxp3 gene expression was analyzed by real-time polymerase chain reaction. The gastric cancer microenvironment was modeled by establishing the co-culture of gastric cancer cell line, MGC-803, with sorting CD4+ T cells. The normal gastric mucosa cell line, GES-1, was used as the control. The production of TGF-β1 was detected in supernatant of MGC and GES-1. The carboxyfluorescein diacetatesuccinimidyl ester (CFSE) dilution assay was performed to evaluate the proliferation characteristics of induced Tregs. Neutralizing anti-TGF-β1 antibody was added to the co-culture system for neutralization experiments.

RESULTS: The level of serum TGF-β1 in gastric cancer patients (15.1 ± 5.5 ng/mL) was significantly higher than that of the gender- and age-matched healthy controls (10.3 ± 3.4 ng/mL) (P < 0.05). Furthermore, the higher TGF-β1 level correlated with the increased population of CD4+Foxp3+ Tregs in advanced gastric cancer (r = 0.576, P < 0.05). A significant higher frequency of CD4+Foxp3+ Tregs was observed in PBMCs cultured with the supernatant of MGC than GES-1 (10.6% ± 0.6% vs 8.7% ± 0.7%, P < 0.05). Moreover, using the purified CD4+CD25- T cells, we confirmed that the increased Tregs were mainly induced from the conversation of CD4+CD25- naive T cells, and induced Tregs were functional and able to suppress the proliferation of effector T cells. Finally, we demonstrated that gastric cancer cells induced the increased CD4+Foxp3+ Tregs via producing TGF-β1. Gastric cancer cells upregulated the production of TGF-β1 and blockade of TGF-β1 partly abrogated Tregs phenotype.

CONCLUSION: Gastric cancer cell can induce Tregs development via producing TGF-β1, by which the existence of cross-talk between the tumor and immune cells might regulate anti-tumor immune responses.

Keywords: Transforming growth factor-β1; Regulatory T cells; Gastric cancer; Immune suppression