Inhibiting effect of Astragalus polysaccharides on the functions of CD4+CD25 highTreg cells in the tumor microenvironment of human hepatocellular carcinoma.

Background: Astragalus polysaccharides (APS), the main active extract from Astragalus membranaceus (a traditional Chinese medicinal herb), is associated with a variety of immunomodulatory activities. The purpose of the present study was to examine the effect of APS on the function of Treg cells in the tumor microenvironment of human hepatocellular carcinoma (HCC) and to identify the pharmacologic mechanism of APS responsible for the anti-chemotactic activity in CD4+CD25highTreg cells in tumor site of HCC.

Methods: The prevalence of Treg in fresh tissue samples from 31 patients with HCC after radicalhepatectomy was detected. CD4, CD25 and CD127 were selected as Treg cell makers to phenotype cell populations. The expression of FOXp3 mRNA was also analyzed. The migration and proliferation of Treg cells were observed. Interleukin (IL)-4, IL-10, IFN-γ and SDF-1 in cell supernatant were detected. For all tests, functions of Treg cells were evaluated after treatment with APS.

Results: APS can inhibit the growth and proliferation of CD4+CD25+Treg cells in vitro in a dose- and time-dependent manner. APS may inhibit CD4+CD25+Treg cells through restoring the cytokine imbalance and reducing the expression of FOXp3 in local HCC microenvironments. SDF-1 played an important role in there recruitment of Treg cells into the tumor microenvironment of HCC. APS might have inhibiting effects on Treg cell migration by blocking SDF-1 or its receptor through the CXCR4/CXCL12 pathway.

Conclusions: The increase in numbers of tumor associated Treg cells might play a role in modulation of the immune response against HCC. APS can restore the cytokine balance in the tumor micro environment and suppress the expression of FOXp3 mRNA to inhibit the immune suppressive effects of Treg cells. The application of APS in the tumor microenvironment might act to enhance the anti-tumor effects of the immunotherapy-based methods, and consequently to increase the survival rate in HCC.