TY - JOUR
T1 - Gastric cancer cells induce human CD4+Foxp3+ regulatory T cells through the production of TGF-β1
AU - Yuan, Xiang Liang
AU - Chen, Lei
AU - Zhang, Tong Tong
AU - Ma, Yan Hui
AU - Zhou, Yun Lan
AU - Zhao, Yan
AU - Wang, Wei Wei
AU - Dong, Ping
AU - Yu, Liang
AU - Zhang, Yan Yun
AU - Shen, Li Song
PY - 2011/4/21
Y1 - 2011/4/21
N2 - 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 car-boxyfuorescein 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 confrmed 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. © 2011 Baishideng. All rights reserved.
AB - 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 car-boxyfuorescein 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 confrmed 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. © 2011 Baishideng. All rights reserved.
KW - Regulatory
KW - Transforming growth factor-β1
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U2 - 10.3748/wjg.v17.i15.2019
DO - 10.3748/wjg.v17.i15.2019
M3 - Article
C2 - 21528082
AN - SCOPUS:79955928676
SN - 1007-9327
VL - 17
SP - 2019
EP - 2027
JO - World journal of gastroenterology
JF - World journal of gastroenterology
IS - 15
ER -