CD45RA-Foxp3high but not CD45RA+Foxp3low suppressive T regulatory cells increased in the peripheral circulation of patients with head and neck squamous cell carcinoma and correlated with tumor progression.

Wei Sun,Wei-Jin Li,Hua Zhong,Wei-Ping Wen,Chang-You Wu

doi:10.1186/1756-9966-33-35

Abstract

BackgroundT regulatory cells (Tregs) contribute to the progression of head and neck squamous cell carcinoma (HNSCC) by suppressing antitumor immunity. However, little is known regarding the functional heterogeneity of Tregs in HNSCC patients.MethodsUsing multicolor flow cytometry, the frequency of three Treg subsets, separated on the basis of CD45RA and Foxp3, from the peripheral circulation of newly-presenting HNSCC patients (19 oral cavity squamous cell carcinoma, 20 hypopharyngeal squamous cell carcinoma, 18 nasopharyngeal squamous cell carcinoma, 19 oropharyngeal squamous cell carcinoma, and 36 laryngeal squamous cell carcinoma) were assessed with regard to 31 healthy donors and clinicopathological features. Moreover, the functional capacity of each Treg subsets was evaluated based on CD45RA and CD25 expression.ResultsThe frequency of Tregs in the peripheral circulation of HNSCC patients as a whole cohort was higher than in healthy donors (P < 0.0001). However, the frequency of Tregs was similar between patients with oral cavity squamous cell carcinoma and healthy donors (P = 0.269). Further dividing Tregs into three subsets based on Foxp3 and CD45RA expression revealed that the frequency of CD45RA-Foxp3high Tregs and CD45RA-Foxp3lowCD4+ T cells in patients with HNSCC developing from different subsites was higher than in healthy donors (P < 0.0001, P < 0.0001), whereas the frequency of CD45RA+Foxp3low Tregs was lower than in healthy donors (P < 0.0001). Functionally study revealed that CD45RA-CD25+++ Tregs significantly inhibit the proliferation of CD4+CD25- T cells (P < 0.001) and secrete lower levels of cytokines (P < 0.01) compared with CD45RA-CD25++CD4+ T cells. Importantly, the frequency of CD45RA-Foxp3high Tregs positively correlate with tumor stage (P < 0.0001) and nodal status (P < 0.0001).ConclusionsCD45RA-Foxp3high Tregs increase in the peripheral circulation of HNSCC patients, and correlate with tumor stage and nodal status; suggesting a role in tumor progression which may be manipulated by future immunotherapy.

Highlights

T regulatory cells (Tregs) contribute to the progression of head and neck squamous cell carcinoma (HNSCC) by suppressing antitumor immunity
Prevalence of three distinct Treg subsets in the peripheral circulation of 112 HNSCC patients Figure 1A illustrates the gating strategy used to identify the frequency of CD25+Foxp3+ Tregs in the total CD3
To understand the heterogeneous role of Tregs, Tregs in the peripheral circulation of 112 HNSCC patients were dissected into three functionally distinct subsets based on the expression of CD45RA, Foxp3, and CD25, and our results showed that the frequency of Tregs in HNSCC patients was higher than in healthy age-matched donors, which is in agreement with previous studies [10,22], both the frequency and function of these three Treg subsets varied in HNSCC patients; i.e., the frequency of CD45RA−Foxp3high suppressive Tregs in HNSCC patients was higher than in healthy donors, whereas the frequency of CD45RA+Foxp3low Tregs was lower, suggesting that CD45RA+Foxp3low Tregs may be swiftly converted into CD45RA−Foxp3high Tregs immediately after migrating from the thymus or having been peripherally generated [14]

Summary

Introduction

T regulatory cells (Tregs) contribute to the progression of head and neck squamous cell carcinoma (HNSCC) by suppressing antitumor immunity. 90% of head and neck cancer cases arise from organs lined by squamous epithelium [2]. It is widely recognized that the progression of head and neck squamous cell carcinoma (HNSCC) is attributed to the peripheral immune tolerance to tumors [4]. Foxp3+CD25+CD4+ T regulatory cells (Tregs), with immunosuppressive activity against tumor-specific T cell responses, are one of the crucial players for immune tolerance [5,6]. Identification of distinct Treg subsets and their functional abilities might be more intriguing in antitumor immunity field

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