Methyl Gallate Exhibits Potent Antitumor Activities by Inhibiting Tumor Infiltration of CD4+CD25+ Regulatory T Cells

Abstract

CD4+CD25+ regulatory T (Treg) cells play crucial roles in the host response to tumors. Increasing evidence supports the existence of elevated numbers of Treg cells in solid tumors and hematologic malignancies. In this study, the effects of methyl gallate on Treg cells were examined. Methyl gallate inhibited Treg cell-suppressive effects on effector CD4+ T cells and Treg migration toward tumor environment. The expression of Treg surface markers including CTLA-4, CCR4, CXCR4, and glucocorticoid-induced TNFR was significantly suppressed upon methyl gallate treatment. Furthermore, forkhead box P3 (Foxp3) expression was also significantly decreased by methyl gallate, suggesting that the suppressive effects of methyl gallate on Treg were medicated by decrease of Treg-specific transcription factor Foxp3. In tumor-bearing hosts, methyl gallate treatment substantially reduced tumor growth and prolonged the survival rate. In contrast, nu/nu mice did not show decreased tumor progression in response to methyl gallate. In addition, in tumor-bearing Treg-depleted mice, tumor growth and the survival rates were not changed by methyl gallate treatment, strongly suggesting that the main therapeutic target of methyl gallate in tumor suppression was related to modulation of the CD4+CD25+ Treg cell functions. In the spleen of tumor-bearing mice, methyl gallate treatment induced a significant decrease in the CD4+CD25+Foxp3high Treg cell population. Especially, the number of tumor-infiltrating CD25+Foxp3high Treg cells was significantly lower in methyl gallate-treated mice. These results suggest that methyl gallate can be used to reverse immune suppression and as a potentially useful adjunct for enhancing the efficacy of immune-based cancer therapy.

Blockade of MCP-1/CCR4 signaling-induced recruitment of activated regulatory cells evokes an antitumor immune response in head and neck squamous cell carcinoma

“…Infiltrating lymphocyte suspensions were prepared by enzymatic digestion [44]. Dissected tumor or adjacent nontumor tissues were minced into small pieces with a scalpel.…”

Home Sweet Home: The Tumor Microenvironment as a Haven for Regulatory T Cells

“…Increased levels of CCL17 and/or CCL22 are also associated with higher frequencies of CD4 + Foxp3 + T cells in cerebral spinal fluid of patients with lymphomatous and carcinomatous meningitis (37), gastric (38), and esophageal squamous cell carcinomas (39). Using mouse models, several approaches, including the use of specific antibodies, antagonists, or siRNA, have been used to block the CCL22/CCL17 – CCR4 axis, resulting in reduction in T reg frequencies and a concomitant increase in anti-tumor activity (40–42). …”

Targeting Regulatory T Cells in Cancer

“…Nevertheless, disruption of CCR5/CCL5 signalling blocks T Reg migration to tumours and inhibits pancreatic tumour growth in mice (28). Methyl gallate has also recently been shown to inhibit infiltration of T Regs into tumours resulting in reduced tumour growth and prolonged survival rates (29). …”