556 6.07 ± 1.81 <0.0001 Statistical comparisons were performed using the Mann–Whitney U-test. Discussion Tregs have been suggested to contribute to HNSCC progression by suppressing antitumor immunity [4]. Although Tregs in the peripheral circulation of HNSCC patients have been investigated

previously, most of these studies were focused on the frequency and suppressive function of CD25+ Tregs or CD25high Tregs [10, 22–24], and the functional heterogeneity of Tregs was not fully investigated. To expand the understanding of functionally distinct Treg subsets in HNSCC, we recruited a cohort of 112 newly-presenting HNSCC patients that had not received any previous treatment for cancer. The use of the CD45, Foxp3, and CD25 markers has allowed both the frequency see more and the function of three distinct Treg subsets in the circulation of HNSCC patients with tumors

selleck screening library of varying stage and nodal status to be determined. There is evidence that Tregs are negative prognostic factors for patients with types of human malignancies [7, 8, 25]. In contrast to these results, however, previous studies of Tregs in HNSCC showed different conclusions. For example, Pretscher et al. [26] showed that higher levels of Tregs do not show any significant influence on outcome of oro- and hypopharyngeal carcinoma patients, and other HNSCC studies even showed that expansion of Tregs is significant prognostic factor related to better locoregional control and Tacrolimus (FK506) overall survival [27, 28]. This apparent confusion regarding the role of Tregs in prognosis of cancer patients might be explained by the functional heterogeneity of Tregs or the nature of tumor type, or some combination of the two. Hence, 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 although 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]. Although we are not aware of this phenomenon in human malignancies, the conversion of CD45RA+Foxp3low Tregs to CD45RA-Foxp3high Tregs has been found in other pathological conditions, such as sarcoidosis [14]. Sakaguchis’s group defined CD45RA-Foxp3lowCD4+ T cells as cytokine-secreting non-Tregs for their ability to secrete several cytokines (IL-2, IL-17, and IFN-γ).