However, this only reached significance for patients with oropharyngeal cancer. It has been demonstrated in previous publications that cells expressing high levels of the IL-2 receptor (CD4+ CD25high) have the capacity to inhibit the proliferation of effector T cells, whereas cells expressing intermediate/low levels of CD25 do not.[20, 37] In contrast, the current study demonstrated that the CD127low/− Treg cell Epigenetics Compound Library population expressing intermediate levels of CD25 consistently induced a greater level of suppression compared with those

cells expressing high levels of the IL-2 receptor, reaching significance for healthy controls and a number of different HNSCC patient subgroups on Autophagy Compound Library both effector T-cell populations. Although not previously assessed in cancer patients, the level of suppression induced by CD127low/− Treg cells separated by different levels of CD25 expression has been examined in healthy controls where it was shown that CD127low T cells expressing high and intermediate/low levels of CD25 both have the capacity to suppress the proliferation of effector T cells to a similar extent.[23, 24, 38] Treg cells are widely accepted as being anergic in vitro but this anergy can be broken under suitable conditions.[39] It is therefore unknown, whether the increase

in suppressive activity observed by the CD25inter Treg cells compared with that induced by the CD25high Treg cells, is a result of their expansion during co-culture or of an increased ability to suppress effector T-cell proliferation. The current study has highlighted how distinct populations of cells, identified on the basis of expression levels of surface markers, show significantly different biological effects; however, these cell populations should not be considered as static entities. For instance Hartigan-O’Connor et al. suggested that the CD25inter CD127low/− cells may contain precursors to fully activated CD25high CD127low/− Treg cells, and demonstrated during 64 hr of stimulation, that the CD25inter CD127low/−

cells up-regulated the expression of CD25 and Foxp3, coupled with down-regulation of CD127.[38] Hence it is conceivable that the Treg cell populations could develop during assay incubation periods and acquire Cobimetinib cost or lose functional capabilities. In summary, newly presenting HNSCC patients with tumours that have metastasized to the lymph nodes have been shown to be associated with an elevated frequency and suppressive activity of peripheral CD25high Treg cells, and patients with advanced stage tumours have been found to have an increased level of Treg cells identified by the same phenotype. In addition, CD25inter Treg cells induced the highest levels of suppression for healthy controls and HNSCC patients, regardless of tumour subsite, stage or nodal involvement.

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