The imbalance of Th17/Treg in patients with uterine cervical cancer

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Abstract

Background

Th17/Treg was reported to play critical roles in immunoregulation, and its imbalance may lead to autoimmune diseases and allergic reactions. Information on Th17/Treg in cancer bearing hosts is still limited.

Methods

We examined the expression of IL-17, Foxp3 and IL-10 in uterine cervical cancer (UCC) patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls by flow cytometry and enzyme-linked immunosorbent assay. Interleukin (IL)-17-producing CD4+ cells as Th17 and CD4+CD25+Foxp3+ cells as Treg were expressed as a percentage of the total CD4+ cells.

Results

Compared with controls, patients with UCC or CIN had a higher proportion of Th17 cells. UCC patients also revealed a significant increase in Treg number and IL-17 and IL-10 concentrations in plasma, while CIN patients did not. Notably, in UCC patients, the increased Th17 prevalence was associated with clinical stage, lymph node metastases and vasoinvasion, while the increased Treg frequency was associated with tumor differentiation. Remarkably, an attractive imbalance of Th17/Treg was observed in UUC and CIN patients. Furthermore, in UCC patients with lymph node metastases or vasoinvasion, the ratio of Th17/Treg was significantly higher than that in negative patients respectively.

Conclusions

Our results indicated a possible role of Th17 in UCC patients correlated to Treg cells, and the imbalance of Th17/Treg may be involved in the development and progression of UCC.

Introduction

Uterine cervical cancer (UCC), which with a high proportion of cases goes through a preinvasive phase (cervical intraepithelial neoplasia, CIN) that can be detectable by clinical methods, is the second most prevalent malignancy in women worldwide [1]. Transmission of human papillomavirus (HPV) high-risk subtypes by sexual intercourse is the prime factor in the etiology of UCC [2], [3]. After high-risk HPV infection, only a limited number of patients' cervical lesions progress via CIN I to CIN III to cervical cancer [4]. Most of the cervical HPV infections are cleared as a result of humoral and cell-mediated immune responses [1]. This indicated that immunoregulation may play the central role in the HPV-induced carcinogenesis.

Recently, Th17 cells and regulatory T cells (Treg cells) have been defined as two distinct CD4+ T subsets from Th1 and Th2 cells, on the basis of their pattern of cytokine production and functions. Th17 cells are characterized as preferential producers of IL-17A (also known as IL-17), IL-17F, IL-21, IL-22, and IL-26 in human [5], [6]. The autocrine activity of IL-21, activation of STAT3, and induction of the orphan nuclear receptor ROR γt are the key regulators of Th17-cell lineage differentiation [7], [8]. In the past few years, Th17 cells and their effector cytokines are increasingly being recognized as key players in inflammation, autoimmunity and allergic reactions [9], [10], [11]. However, the nature of Th17 cells is elusively understood in cancer patients. Results from two studies in prostate and ovarian cancer patients have suggested both beneficial and harmful implications of Th17 cells in tumor development [12], [13], while in another research about ovarian cancer, Kryczek et al. [14] showed that Th17 cells may provide protection to human tumor immunity through inducing Th1-type chemokines and recruiting effector cells to the tumor microenvironment. Up to date, however, there is no data about Th17 in patients with UCC.

Treg cells, which are characterized by expressing Foxp3 in the nuclei, are functionally immunosuppressive subset of T cells. They play pivotal roles in inducing T-cell tolerance by contact-dependent suppression or releasing anti-inflammatory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β [15]. This vitally important function exists alongside the detrimental effects on tumor immunosurveillance and antitumor immunity [16]. Evidences from cancer patients suggest that increased Treg activity may be associated with poor immune responses to tumor antigens and contribute to immune dysfunction [17]. In addition, the high number of Treg cells in several human tumors was described to be associated with reduced survival [3], [18]. These studies suggested that Treg cells may suppress antitumor immune response. However, whether Treg cells comprise a higher proportion of peripheral blood lymphocytes of patients with UCC, which reflects the generalized immune status has not been investigated.

The balance between Treg and Th17 cells controls immune response and has been reported to be a key factor in regulating helper T cell function relating to the Th1⁄Th2 shift in autoimmune disease and graft vs host disease [19]. However, there is limited information on the balance between Treg and Th17 cells in cancer patients [14]. To assess whether this balance was broken in patients with UCC, and investigate the possible role of Th17⁄Treg in the pathogenesis and progression of UCC, we measured the levels of Th17 cells and correlated its levels to Treg cells in UCC patients, CIN patients and healthy controls by flow cytometry. This study could help in understanding the possible roles of the imbalance between regulatory and effector cells (Th17 cells) in the development and progression of uterine cervical cancer.

Section snippets

Patients and controls

Forty-nine untreated UCC patients with active disease (age range 34–70 years, median 44 years) and 25 untreated CIN patients (28–60 years, median 42 years) were enrolled in this study. Patients complicated with diabetes, hypertension, cardiovascular diseases, pregnancy, active or chronic infection, connective tissue diseases or have malignant tumor in the past history, were excluded. None of the patients were previously treated with immunosuppressive, radiotherapy or chemotherapy. The

Elevated circulating Th17 frequencies in untreated UCC and CIN patients

We analyzed the expression of IL-17 on CD3+CD8 T cells (Th17 cells) based on cytokine patterns after in vitro activation by PMA/ionomycin in short-term cultures. The expression of a typical dotplot of IL-17 gated on CD3+ T cells in representative patients and controls was shown in Fig. 1A, c–e. As shown in Fig. 2a, the percentage of Th17 cells was significantly increased in UCC patients (2.32 ± 0.85%) and CIN patients (2.05 ± 0.92%) compared to healthy controls (1.21 ± 0.50%, PUCC < 0.0001; PCIN = 

Discussion

Immune escape is a crucial feature of cancer progression [21]. The mechanisms that cause tumor escape have been extensively discussed and include T-cell suppression or dysfunction [22], [23]. Since discovery, Treg cells have gained much attention in antitumor immunity [21], [24], due to the strong immune suppressive activity on T cell responses. Increasing evidence demonstrated that the levels of Foxp3+ Treg cells increased in cancer patients, and the high number of them led to poor survival [3]

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Nos. 30400475 and 81070407), the Shandong Technological Development Project (Nos. 2006BS03060, Q2008C07 and BS2009SW014), the Scientific Research Foundation (SRF) for the Returned Overseas Chinese Scholars (ROCS), the State Education Ministry (SEM), and Independent Innovation Foundation of Shandong University (2009TS063).

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