TGF-β1 promotes colorectal cancer immune escape by elevating B7-H3 and B7-H4 via the miR-155/miR-143 axis.
Transforming growth factor-beta 1 (TGF-β1) suppresses T cell function, promoting tumor immune escape. Yet, whether the depression of TGF-β1 on T cell function is mediated by co-inhibitory molecules B7-H3 and B7-H4 remains largely unclear. Here, we demonstrated that TGF-β1 elevated the expression of miR-155 in colorectal cancer cells through SMAD3 and SMAD4. The upregulated miR-155 attenuated miR-143 by inhibiting its direct target, the transcription factor CEBPB. Consequently, the direct target genes of miR-143, B7-H3 and B7-H4, were augmented in the cytoplasm and membrane of tumor cells. Over-expression of B7-H3 and B7-H4 in HCT-116 cells induced T cells to secrete TGF-β1 and the immunosuppressive cytokines IL-2, IL-6, and IL-17. Restoration of miR-143 inhibited the growth of HCT-116 xenograft tumors in mice, and also repressed the expression of B7-H3 and B7-H4 in the tumors. Thus, this study reveals the mechanism by which TGF-β1 leads to T cell-mediated tumor evasion through an increase in B7-H3 and B7-H4 expression.
Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Xinru
X
Zhou
Department of Oncology, The Fourth Affiliated Hospital of Soochow University, Wuxi, China.
Yong
Y
Mao
Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Jianjie
J
Zhu
Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Fanyi
F
Meng
Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Qi
Q
Chen
Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Lihua
L
Tao
Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Rui
R
Li
Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Fengqing
F
Fu
Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Cuiping
C
Liu
Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China.
Yuanjia
Y
Hu
Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Weipeng
W
Wang
Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Hongjian
H
Zhang
Department of Oncology, The Fourth Affiliated Hospital of Soochow University, Wuxi, China.
Dong
D
Hua
Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Weichang
W
Chen
Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Xueguang
X
Zhang
D000818:Animals; D060887:B7 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000096:biosynthesis
D060887:B7 Antigens; C423237:CD276 protein, human; C542359:MIRN143 microRNA, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human
TGF-β1; co-inhibitor; colorectal cancer; microRNA; tumor evasion