Foxp3 expression in melanoma cells as a possible mechanism of resistance to immune destruction

Abstract

The forkhead transcription factor Foxp3 is the only definitive marker of CD4(+)CD25(+) regulatory T cells (Tregs) and has been identified as a key regulator in the development and function of Tregs. Foxp3 expression has been reported in a variety of solid tumors, including melanoma. In this study, we validated Foxp3 expression in both tumor-infiltrating Tregs and melanoma cells by performing immunohistochemical analysis of human melanoma tissue sections. Further, we assessed Foxp3 expression in melanoma cell lines by performing flow cytometry, confocal microscopic analysis, reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting. Inhibition of Foxp3 expression in melanoma cells using small interfering RNA (siRNA) resulted in downregulation of B7-H1 and transforming growth factor (TGF)-β expression; in contrast, Foxp3 overexpression resulted in the upregulation of the expression of these proteins. Coculture of Foxp3-expressing melanoma cells with naive CD4(+)CD25(-) T cells resulted in strong inhibition of T-cell proliferation. This antiproliferative effect was partially abrogated by specific inhibition of Foxp3 expression and was effectively enhanced by overexpression of Foxp3. We observed an attenuated antiproliferative effect even when melanoma cells and T cells in the coculture were separated using Transwell inserts. These findings indicated that melanoma cells could have Foxp3-dependent Treg-like suppressive effects on T cells and suggested that the mimicking of Treg function by melanoma cells may represent a possible mechanism of tumor resistance to immune destruction in the melanoma tumor microenvironment.

FOXP3 autoantibody as a potential early prognostic serum biomarker in patients with cervical cancer

“…Thus, serum autoantibodies are sensitive biomarkers for cancer detection [18]. For immune response between TAAs and autoantibodies present in cancer patients, the detection of serum autoantibodies can be used to distinguish between cancer patients and healthy subjects [19,20]. Many studies on lung, stomach and colon cancers have confirmed that TAAs and TAA autoantibodies can be used as tools for early diagnosis of cancer and indicators of therapeutic efficacy.…”

FOXP3 Expression Is Related to High Ki-67 Index and Poor Prognosis in Lymph Node-Positive Breast Cancer Patients

“…Candidate mechanisms by which FOXP3 contributes to therapy resistance and poor prognosis include induction of immune evasion by inhibiting immune response against the tumor, promoting metastasis by regulating chemokine receptors, and downregulation of genes such as PDE3B, which is reported to prevent apoptosis of T cells [15]. Several studies in malignant melanoma, pancreatic cancer and inflammatory breast cancer have shown that FOXP3-positive cancer cells induce immune evasion by mimicking immune cells, and FOXP3-targeted immune therapy has demonstrated considerable efficacy in preclinical models [16,17]. The immune evasion property of cancer cells is receiving more attention from researchers as an emerging hallmark of cancer [18].…”

FOXP3 over-expression inhibits melanoma tumorigenesis via effects on proliferation and apoptosis.

“…This has been demonstrated in pancreatic carcinoma and melanoma cell lines, where FOXP3 expression inhibits T cell proliferation in co-culture systems [5, 8]. FOXP3 expression in tumors was also shown to be associated with worse overall survival in breast, bladder, and colorectal cancer patients [11, 22, 23].…”

“…Specifically, FOXP3 expression has been reported in normal breast, prostate and ovarian epithelium, and to be down-regulated in the corresponding tumor tissue [2-4]. Conversely, increased FOXP3 expression has been reported in pancreatic adenocarcinoma [5], melanoma [6-8], hepatocellular carcinoma [9], leukemia [10], bladder cancer [11], thyroid carcinoma [12] and cervical cancer [13], with no expression in corresponding normal tissue. These findings suggest either a pro- or anti-tumorigenic role, depending on the tumor type.…”