Abstract
BackgroundThe signal transducer and activator of transcription 3 (STAT-3) is frequently overexpressed in cancer cells, propagates tumorigenesis, and is a key regulator of immune suppression in cancer patients. The presence of phosphorylated STAT-3 (p-STAT-3) in the tumor can induce p-STAT-3 in tumor-associated immune cells that can return to the circulatory system. We hypothesized that the number of peripheral blood mononuclear cells (PBMCs) displaying p-STAT-3 would be increased in glioma patients, which would correlate with the extent of tumor-expressed p-STAT-3, and that higher p-STAT-3 levels in peripheral blood would correlate with a higher fraction of immune-suppressive regulatory T cells (Tregs).MethodsWe measured the percentage of PBMCs displaying p-STAT-3 in 19 healthy donors and 45 patients with primary brain tumors. The level of p-STAT-3 in tumor tissue was determined by immunohistochemistry. The degree of immune suppression was determined based on the fraction of Tregs in the CD4 compartment.ResultsHealthy donors had 4.8 ± 3.6% of PBMCs that expressed p-STAT-3, while the mean proportion of PBMCs displaying p-STAT-3 in patients with GBM was 11.8 ± 13.5% (P = 0.03). We did not observe a correlation by Spearman correlation between the degree of p-STAT-3 levels in the tumor and the percent of PBMCs displaying p-STAT-3. Furthermore, the percent of PBMCs displaying p-STAT-3 in glioma patients was not directly correlated with the fraction of Tregs in the CD4 compartment.ConclusionWe conclude that the percent of PBMCs displaying p-STAT-3 may be increased in malignant glioma patients.
Highlights
The signal transducer and activator of transcription 3 (STAT-3) is frequently overexpressed in cancer cells, propagates tumorigenesis, and is a key regulator of immune suppression in cancer patients
Γ-IFN has been shown to be down-regulated by p-STAT-3 [15] and γ-IFN levels have been shown to be decreased in glioma patient peripheral blood mononuclear cell (PBMC) [24]
We have shown that p-STAT-3 blockade in immune cells restores immune responses [25] and inhibits regulatory T cells (Treg) induction [26]
Summary
The signal transducer and activator of transcription 3 (STAT-3) is frequently overexpressed in cancer cells, propagates tumorigenesis, and is a key regulator of immune suppression in cancer patients. The phosphorylated STAT-3 (pSTAT-3) translocates into the nucleus and induces a variety of transcriptional factors that propagate tumorigenesis [1] and up-regulate tumor-mediated immunosuppressive factors [2] These factors include IL-10 [6,7] that adversely influences Th1-mediated cytotoxic immune responses at multiple levels and is essential for regulatory T cells (Tregs) function [8,9], vascular endothelial growth factor [10] that inhibits dendritic cell maturation and activation by inhibiting co-stimulatory molecule expression [11], PGE2 [12] that induces the immune suppressive Th17 cell [13], and TGF-β [14] that induces Tregs, inhibits T cell proliferation and down-modulates the IL-2 receptor. P-STAT-3 regulates immune suppression and tumor progression via multiple redundant mechanisms [18,22,23,27,28]
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