Abstract 5000: Tolerogenic transcription regulator Foxp3 controls the expression of immunosuppressive cytokines in melanoma cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-04, Vol.71 (8_Supplement), p.5000-5000
• Main Authors: Olson, Samuel Y., Chen, Cynthia, Marquez, Diana C., Bruhn, Kevin W., Craft, Noah A., Garban, Hermes J.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-5000

Foxp3 is a critical transcription regulator that is found commonly expressed in a subset of immunosuppressive CD4+/CD25+ T cells characterized as regulatory T cells (Tregs) in the immune system. Foxp3 is a member of the forkhead/winged-helix family of transcriptional regulators exhibiting both, activation and repression of transcription. Foxp3 is critically important for the development and function of Tregs and the consequent definition of immune-tolerance. Ectopic Foxp3 expression has been shown to -phenotypically and functionally- convert T cells to Tregs. Recently, we have characterized the expression of Foxp3 in a variety of human and mouse cancerous cells, either in tissue or in cultured cell lines. Although of cardinal importance, the specific role and mechanisms involved in the Foxp3-mediated immunosuppressive activity remains elusive. Thus, we hypothesize that tumor-derived Foxp3 is controlling the transcriptional expression of immunosuppressive cytokines by tumor cells and inducing immunotolerance in the tumor microenvironment. We have tested this hypothesis by interrogating the well-characterized B16-C57BL/6 syngeneic mouse model of melanoma. Foxp3-expressing B16-F0 cells (B16-Foxp3+) where specifically and stably knockdown for Foxp3 expression by lentivirus-mediated shRNA (B16-Foxp3-). In order to determine the specific role and mechanisms of melanoma-derived Foxp3 in controlling the expression of immunosuppressive cytokines generated by melanoma cells, we have evaluated the differential cytokine expression profile between the B16Foxp3+ and the B16-Foxp3- cultured cells using Multiplex Bead Immunoassay, Immunoblotting Assay of Proteins and Semiquantitative RT-PCR. Our results demonstrated that the suppression of expression of Foxp3 in melanoma cells showed a significant downregulation of a selected group of immunosuppressive cytokines, in particular IL-4, IL-6, IL-10, IL-12, TNF-alpha and GM-CSF. In contrast, Foxp3 did not have an appreciable effect on the expression of IL-1, IL-2, IL-5, and IFN-gamma. Altogether, our data suggest the specific role of tumor-derived expression of FOXP3 in the control of the expression of tolerogenic/immunosuppressive cytokines secreted by melanoma cells to the tumor microenvironment. Furthermore, selective suppression of Foxp3 expression and/or activity in cancerous cells may help to develop better and more effective targeted immunotherapy as treatment for malignant melanoma. Citation Format: {Authors}. {Abstrac