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. 2011;6(9):e24671.
doi: 10.1371/journal.pone.0024671. Epub 2011 Sep 14.

Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis

Kang-Jie Chen  1 , Sheng-Zhang Lin, Lin Zhou, Hai-Yang Xie, Wu-Hua Zhou, Ahmed Taki-Eldin, Shu-Sen Zheng
Affiliations

Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis

"V体育2025版" Kang-Jie Chen et al. PLoS One. 2011.

"VSports注册入口" Abstract

Background: Regulatory T cells (Tregs) are highly prevalent in tumor tissue and can suppress effective anti-tumor immune responses VSports手机版. However, the source of the increased tumor-infiltrating Tregs and their contribution to cancer progression remain poorly understood. .

Methodology/principal finding: We here investigated the frequency, phenotype and trafficking property of Tregs and their prognostic value in patients with hepatocellular carcinoma (HCC). Our results showed that FoxP3(+) Tregs highly aggregated and were in an activated phenotype (CD69(+)HLA-DR(high)) in the tumor site, where they can suppress the proliferation and INF-γ secretion of CD4(+)CD25(-) T cells. These tumor-infiltrating Tregs could be selectively recruited though CCR6-CCL20 axis as illustrated by (a) high expression of CCR6 on circulating Tregs and their selective migration to CCR6 ligand CCL20, and (b) correlation of distribution and expression between tumor-infiltrating Tregs and intratumoral CCL20. In addition, we found that the number of tumor-infiltrating Tregs was associated with cirrhosis background (P = 0. 011) and tumor differentiation (P = 0. 003), and was an independent prognostic factor for overall survival (HR = 2. 408, P = 0. 013) and disease-free survival (HR = 2. 204, P = 0 V体育安卓版. 041). The increased tumor-infiltrating Tregs predicted poorer prognosis in HCC patients. .

Conclusions: The CCL20-CCR6 axis mediates the migration of circulating Tregs into tumor microenvironment, which in turn results in tumor progression and poor prognosis in HCC patients V体育ios版. Thus, blocking CCL20-CCR6 axis-mediated Treg migration may be a novel therapeutic target for HCC. .

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Conflict of interest statement (V体育ios版)

Competing Interests: The authors have declared that no competing interests exist.

"VSports注册入口" Figures

Figure 1
Figure 1. CD4+CD25+FoxP3+ Tregs are highly enriched in tumors of HCC patients.
Tregs (CD4+CD25+ T cells) were gated from CD3+ T cells by flow cytometry. (a, b) Representative plots (a) and statistical analysis (b) show that the frequency of CD4+CD25+ T cells was higher in HCC patients, especially among TIL. The percentages in (a) represent the frequency of CD4+CD25+ T cells among CD4+ T cells. The data in (b) are expressed in box plots, in which the horizontal lines illustrate the 25th, 50th and 75th percentiles. (c, d) Representative images (c) and statistical analysis (d) of immunohistochemical staining of FoxP3+ lymphocytes in the tumor and non-tumor tissue from HCC patient and normal control liver. Magnification, ×200. The data in (d) show that the number of FoxP3+ cells is significantly higher in tumor than in non-tumor or normal control. hpf, high-powered field. (e) Statistical analysis shows FoxP3+ cells preferentially aggregate in the parenchyma of tumors.
Figure 2
Figure 2. Phenotypic and functional analysis of CD4+CD25+ Tregs in HCC patients.
(a) Representative FoxP3, CTLA-4, CD45RO, CD69 and HLA-DR expression profiles in CD4+CD25+ (thick line) and CD4+CD25− (dotted line) T cells from the four studied groups. Specific isotypes were used as negative control. The percentages represent the frequencies of various markers on CD4+CD25+ T cells. The italic numerical values represent MFI of FoxP3 in CD4+CD25+ T cells. (b) Statistical analysis shows that the MFI of FoxP3 in CD4+CD25+ T cells from TIL was significantly higher than those from NIL, cPBMC, and nPBMC. *P<0.05, compared with TIL. (c) Purified CD4+CD25+ T cells (Tregs) from TIL, NIL, and cPBMC could similarly inhibit the proliferation and INF-γ production of autologous CD4+CD25− T cells (Tconv) in a dose-dependent manner (n = 3 for each group). *P<0.05; **P<0.01, compared with autologous controls (Treg∶Tconv = 0∶1). Data in (b) and (c) represent the mean±S.E.M.
Figure 3
Figure 3. Increased CCL20, secreted by liver tumor cells, is associated with the number of tumor-infiltrating Tregs.
(a) Real-time PCR of selective chemokines in tumor and non-tumor regions of HCC patients and in normal control liver. The value was normalized to GAPDH, multiplied by 105, and log transformed. (b) immunohistochemical staining of chemokine CCL20 (brown, cytoplasm). Numerous CCL20-secreting tumor cells are seen in tumor region, and a few CCL20-secreting Kuffer cells in non-tumor region. Magnification, ×200; insert boxes, ×400. (c) Statistical analysis shows the CCL20 level in tumor tissue is significantly stronger than that in non-tumor and normal liver tissues. IOD, integrated optical density. (d) The correlations between CCL20 level and the number of FoxP3+ cells in tumor (left) and non-tumor (right) regions. The expression of CCL20 and FoxP3 were detected by immunohistochemical staining, and quantified as described in “Materials and Methods”. (e) Double staining of CCL20 (red, cytoplasm) and FoxP3 (brown, nucleus). The regions expressing high and low levels of CCL20 are marked by “★” and“*”, respectively. Big arrows indicate CCL20-secreting tumor cells, and small arrows FoxP3+ cells. Magnification, ×200, left; ×400, right.
Figure 4
Figure 4. Circulating CD4+CD25+ Tregs in HCC patients highly express CCR6, and selectively migrate to tumors under recruitment of CCL20.
(a) Representative plots of CCR6, CCR4 and CCR7 on CD4+CD25+ (solid line) and CD4+CD25− (dotted line) T cells from different compartments. Specific isotypes were used as negative control. The percentages represent frequencies of CCR6, CCR4 and CCR7 on CD4+CD25+ T cells. (b) Statistical analysis shows that cPBMC-derived CD4+CD25+ Tregs expressed significantly higher CCR6 than autologous CD4+CD25− T cells or Tregs from the other groups. **P<0.01, ***P<0.001. (c) CD4+CD25+ T cells migrate in response to recombinant human CCL20 or supernatant of SMMC-7721 cells (n = 3). A specific antibody to CCL20 significantly inhibits CD4+CD25+ T cell migration. Data represent the mean±S.E.M. **P<0.01, ***P<0.001.
Figure 5
Figure 5. Differential expression of CD11a, CD62L and CD103 on CD4+CD25+ Tregs.
(a) Representative CD11a, CD62L, and CD103 expression profiles on CD4+CD25+ (solid line) and CD4+CD25− (dotted line) T cells from the four studied groups. Specific isotypes were used as negative control. The percentages represent the frequencies of various markers on CD4+CD25+ T cells. The italic numerical values represent MFI of CD11a on CD4+CD25+ T cells. (b–d) Statistical analyses of CD11a intensity (b), as well as CD62L (c) and CD103 (d) frequencies on CD4+CD25+ Tregs. The data are expressed in box plots, in which the horizontal lines illustrate the 25th, 50th and 75th percentiles. *P<0.05, **P<0.01, ***P<0.001.
Figure 6
Figure 6. Accumulation of tumor Treg cells predicts poor survival in patients with hepatocellular carcinoma.
The cumulative overall survival and disease-free survival of HCC patients were estimated using the Kaplan-Meier method and compared by the log-rank test. Patients with high FoxP3+ Tregs (dashed lines) had significantly poorer survival compared with individuals with low FoxP3+ Treg density (solid lines).
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