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. 2007 Feb 26;96(4):617-22.
doi: 10.1038/sj.bjc.6603580. Epub 2007 Jan 30.

Increase in circulating Foxp3+CD4+CD25(high) regulatory T cells in nasopharyngeal carcinoma patients

K-M Lau  1 , S H Cheng, K W Lo, S A K W Lee, J K S Woo, C A van Hasselt, S P Lee, A B Rickinson, M H L Ng
Affiliations

Increase in circulating Foxp3+CD4+CD25(high) regulatory T cells in nasopharyngeal carcinoma patients

K-M Lau et al. Br J Cancer. .

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated disease with high prevalence in Southern Chinese. Using multiparametric flow cytometry, we identified significant expansions of circulating naïve and memory CD4+CD25(high) T cells in 56 NPC patients compared with healthy age- and sex-matched controls. These were regulatory T cells (Treg), as they overexpressed Foxp3 and GITR, and demonstrated enhanced suppressive activities against autologous CD4+CD25- T-cell proliferation in functional studies on five patients. Abundant intraepithelial infiltrations of Treg with very high levels of Foxp3 expression and absence of CCR7 expression were also detected in five primary tumours. Our current study is the first to demonstrate an expansion of functional Treg in the circulation of NPC patients and the presence of infiltrating Treg in the tumour microenvironment. As Treg may play an important role in suppressing antitumour immunity, our findings provide critical insights for clinical management of NPC.

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Figures

Figure 1
Figure 1
Characterisation of the Treg populations in PB of NPC patients and normal healthy blood donors. Gating of CD4+CD25+ (R2 and R3 gated regions) and CD4+CD25high (R3 gated region) T cells of representative normal individual control (A) and NPC patient (B) are presented. The Foxp3-expressed T cells (coloured in black) were back-gated among the lymphocytes (coloured in grey) in the FASC plots. Percentages of circulating CD3+CD4+CD25+ T cells (C) and CD3+CD8+CD25+ T cells (D) in lymphocytes were determined in 56 NPC patients (▪) and 56 age- and sex-matched normal controls (▴).The CD3+CD4+CD25high T-cell populations were also gated and the percentages between two groups were compared (E). The horizontal lines represent the mean values of the cell percentages. Expression levels of various Treg markers such as CTLA-4/CD152 (F), GITR (G), and Foxp3 (H) in the cells were also examined. Expression levels in terms of mean fluorescence intensity of these markers in representative cases of normal (yellow line) and NPC patients (green line) are shown. The differences in mean values of two groups were statistically analysed by Mann–Whitney U test and the significance level is set at 0.05. Asterisks indicate that the mean percentages of T-cell subsets in lymphocytes of NPC patients showed statistically significant differences as compared to those in controls. (I) Functional characterisation of circulating Treg in healthy volunteers (N=4) and NPC patients (N=5, four from the group of 56 patients and one was also analysed for TIL but not for PB Treg). CD4+CD25− T cells (2 105/ml) were challenged with CD3 antibody and levels of cellular proliferation determined in the presence or absence of autologous Treg added at the ratios indicated. Mean levels of cellular proliferation are expressed as a percentage of that seen in cultures without the addition of Tregs. The mean percentages of CD4+CD25+ Treg, which can achieve 50% inhibition of autologous CD4+CD25− T-cell proliferation, were compared (right). The standard deviations of the percentages were presented as ‘T’ bars.
Figure 2
Figure 2
Characterising Treg in TIL and PB. The biopsy specimen was mechanically dissociated, fixed, and immunostained with the antibodies to CD4, CD25, and Foxp3 or CCR7. The suspended cells were analysed by flow cytometry gating on lymphocytes. Flow cytometric analysis on PB was as previously described in Figure 1. Two representative cases (NPC1 and NPC2) are shown. The percentage of Tregs was explored in TIL(▪) and PB (□) analysing the CD4+CD25+ gated population (R2 and R3) and the CD4+CD25high population (R3 alone). Expression of Foxp3 and CCR7 in CD4+CD25high Treg from both TIL and PB are presented as histograms. For these histograms, they are the composite of two different FACS plots, one from the data of PB (white coloured peak) and another from TIL (black coloured peak), highlighting the loss of CCR7 expression and increased Foxp3 expression in the CD4+CD25high of TIL as the shifts of those peaks. The horizontal line represents the cutoff of positivity defined using an isotype-matched control antibody.
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