Importantly, further investigation within the tumor microenvironment showed that expression of Foxp3 in Treg cells correlated with expression of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)).
CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors.
In surgical specimens of less differentiated HCC, the quantity of tumor-infiltrating FoxP3(+) Tregs was significantly lower and IL-17(+) T cells and CD8(+) T cells were significantly higher.
We discovered that the immune regulatory effect of C-MYC and PD-L1, and the tumor suppressor function of tumoral FOXP3 had a significant influence on the tumor microenvironment (Tregs, CD8 + T cells, and tumor infiltrating lymphocytes) in a complex manner.
Tumor-infiltrating lymphocytes (TILs) that test positive for forkhead box P3 (FOXP3) and elevated preoperative serum albumin levels have been positively associated with survival in colorectal cancer (CRC).
TSR was positively associated with stromal PD-L1 expression, the Immunoscore and CD3+ as well as CD4+ TILs density, but negatively correlated with tumor microvessel density, Ki-67 index, surrounding muscle invasion by tumor and number of Foxp3+ and PD-1+ TILs.
The gene expression of CD4, CD8A and forkhead box protein P3 in the tumor was increased compared with healthy breast tissue, and was positively associated with the prognosis of breast cancer patients.
FACS was used to determine the frequencies of Tregs, MDSCs, CD4<sup>+</sup> IFN-γ<sup>+</sup> T cells, and CTLs in the tumors and spleens of the mice. mRNA levels of the transcription factors T-bet and FOXP3 and cytokines IFN-γ, TNF-α, TGF-β, and IL-10 were also determined by real-time RT-PCR.
The transcription factor FOXP3 has been identified as a tumour suppressor in the breast and prostate epithelia, but little is known about its specific mechanism of action.
We have developed and validated quantitative immunohistochemistry (IHC) assays for CD3, CD8 and FOXP3 for immunophenotyping T-lymphocytes in tumor tissue.
In addition to its role as an essential transcription factor in regulatory T cells, the FOXP3 gene is an epithelial cell-intrinsic tumor suppressor for breast and prostate cancers.
Finally, the effects of altering DNMT1 levels in T-cells seemed to affect tumor growth through alteration of methylation status of Foxp3 on promoter and CpG regions.
In addition to its immune suppressive function in T-regulatory cells, the nuclear transcription factor, FOXP3, has been identified as a tumor suppressor.
The presence of CD3 or of FoxP3 infiltrating cells with PD-L1 in patient tumors did not impact the significance of the association of PD-L1 with high grade tumors (P = 0.040), and our analyses did not show an association between the presence of PD-1 or PD-L1 and survival.
Our results showed that FoxP3(+) Tregs highly aggregated and were in an activated phenotype (CD69(+)HLA-DR(high)) in the tumor site, where they can suppress the proliferation and INF-γ secretion of CD4(+)CD25(-) T cells.
The data were correlated to different TIL subset counts (CD3, CD8, GranzymeB, FoxP3 and CD20) and to infiltrating histiocytes (CD68) both in the tumor and the surrounding stromal tissue that were reported earlier.
Tumor heterogeneity and stronger positive TIL associations were found in the non-relapse group, where both CD3-CD8 and FoxP3-Ki67 inter-correlations were found to be significant at the center of the tumor, while the correlation between C3FR and C8FR was significant at the invasive edge.
A double staining of CD8+ cytotoxic T cells (CTL) and FoxP3+ (Treg) was performed and the cell density was evaluated in the intraepithelial and stromal compartment of the tumor.