Research Paper Volume 11, Issue 8 pp 2343—2351
Epigenetic control of Foxp3 in intratumoral T-cells regulates growth of hepatocellular carcinoma
- 1 Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- 2 Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China
- 3 Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Received: February 14, 2019 Accepted: April 10, 2019 Published: April 21, 2019https://doi.org/10.18632/aging.101918
How to Cite
Copyright: Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Capability of tumor cells to impede immune response are largely associated with their interaction and regulation of CD4+CD25+ forkhead box transcription factor (Foxp)3+ regulatory T (Treg) cells, which suppress cytotoxic T cell-mediated immunity in the tumor microenvironment. Foxp3 level is critical for development and phenotypic maintenance of Treg, and is regulated by transcriptional control and epigenetic modification. Here, we showed that higher percentage of intratumoral Treg cells was positively correlated with lower Foxp3 promoter methylation in hepatocellular carcinoma (HCC), and both of them were associated with higher tumor grade, larger tumors, and poor prognosis of the patients. We used an adeno-associated virus (AAV) carrying either DNA (cytosine-5)-methyltransferase 1 (DNMT1) or shDNMT1 under a CD4 promoter (AAV-pCD4-DNMT1, AAV-pCD4-shDNMT1) to successfully target T-cells and alter the levels of DNMT1. Intratumoral injection of AAV- pCD4-DNMT1 significantly reduced tumor growth in mice, while intratumoral injection of AAV- pCD4-DNMT1 significantly induced tumor growth, compared to injection of control AAV. Finally, the effects of altering DNMT1 levels in T-cells seemed to affect tumor growth through alteration of methylation status of Foxp3 on promoter and CpG regions. Together, these data suggest that epigenetic control of Foxp3 in intratumoral T cells regulates growth of HCC.