Inhibition of A20 expression in tumor microenvironment exerts anti-tumor effect through inducing myeloid-derived suppressor cells apoptosis.

Abstract

Myeloid-derived suppressor cells (MDSCs) are known to play important roles in the development of immunosuppressive tumor microenvironment. A20 is a zinc-finger protein which could negatively regulate apoptosis in several cell types. However, the role of A20 in tumor microenvironment remains largely unknown. In this study, we found that A20 was over-expressed in MDSCs. The treatment of tumor-bearing mice with small interfering RNA targeting A20 (si-A20) inhibited the growth of tumors. The infiltration of MDSCs was dramatically reduced after si-A20 treatment, as compared to control groups, whereas the numbers of dendritic cells and macrophages were not affected. Also, injection of si-A20 improved T cell mediated tumor-specific immune response. Depletion of MDSCs with anti-Gr1 antibody showed similar antitumor effect and improved T cell response. TNF-α was highly expressed after si-A20 injection. Furthermore, si-A20 induced apoptosis of MDSCs in the presence of TNF-α both in vivo and in vitro. Cleaved Caspase-3 and Caspase-8 were elevated with the activation of JNK pathway after the induction of MDSC apoptosis by si-A20. Thus, our findings suggested that knockdown of A20 in tumor site inhibited tumor growth at least through inducing the apoptosis of MDSCs. A20 might be a potential target in anticancer therapy.

• Authors: Bin Shao, Xiawei Wei, Min Luo, Jiayun Yu, Aiping Tong, Xuelei Ma, Tinghong Ye, Hongxin Deng, Yaxiong Sang, Xiao Liang, Yu Ma, Qinjie Wu, Wei Du, Jing Du, Xiang Gao, Yi Wen, Ping Fu, Huashan Shi, Shuntao Luo, Yuquan Wei
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 16437 (Nov 12 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26561336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• RNA, Small Interfering
• Tumor Necrosis Factor alpha-Induced Protein 3
• Cysteine Endopeptidases
• Tnfaip3 protein, mouse

Topics

• Animals
• Apoptosis (genetics, immunology)
• Cell Line, Tumor
• Cysteine Endopeptidases (genetics)
• Disease Models, Animal
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Immune Tolerance
• Intracellular Signaling Peptides and Proteins (genetics)
• Lymphocyte Activation (genetics, immunology)
• MAP Kinase Signaling System
• Melanoma, Experimental
• Mice
• Myeloid Cells (immunology, metabolism)
• Neoplasms (genetics, immunology, metabolism, pathology)
• RNA, Small Interfering (genetics)
• T-Lymphocytes (immunology, metabolism)
• Tumor Microenvironment (genetics, immunology)
• Tumor Necrosis Factor alpha-Induced Protein 3