Abstract
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.
Highlights
Accumulating data suggest that tumor cells are capable of developing a variety of strategies to impede immune responses, which allows the tumor cells to grow and invade with exemption from the attacks from immune cells in the body [1]
Treg cells are characterized by the expression of the Forkhead box transcription factor Foxp3, which is a lineage-specifying factor, and exerts specific functionality associated with immunosuppression in this T-cell subpopulation [3]
We showed that in hepatocellular carcinoma (HCC), higher percentage of intratumoral Treg cells was positively correlated with lower Foxp3 promoter methylation, and both of them were associated with higher tumor grade, larger tumors, and poor prognosis of the patients
Summary
Accumulating data suggest that tumor cells are capable of developing a variety of strategies to impede immune responses, which allows the tumor cells to grow and invade with exemption from the attacks from immune cells in the body [1]. Many of these strategies that tumor cells use to escape killing are associated with their interaction and regulation of regulatory T (Treg) cells [2]. Treg cells are characterized by the expression of the Forkhead box transcription factor Foxp, which is a lineage-specifying factor, and exerts specific functionality associated with immunosuppression in this T-cell subpopulation [3]. Treg cells reversibly suppress cytotoxic T cellmediated immunity in the tumor microenvironment, resulting in outgrowth and increased invasiveness of the tumor [7]
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