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Targeting FOXP3 in glioblastoma: Blockade of tumor intrinsic effects boosts response to chemo-radiotherapy
Matías Garcia Fallit1, Jorge A Peña Agudelo2, Alejandro J Nicola Candia2
1Universidad de Buenos Aires, Facultad de Medicina, Departamento de Biología Celular e Histología, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina; Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
Abstract:
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Although this disease carries a dismal prognosis due to its highly invasive nature and resistance to therapy, no significant therapeutic advances have emerged in the last 20 years. The transcription factor Forkhead box protein P3 (FOXP3), known for its central role in the immunosuppressive activity of regulatory T cells (Tregs), has also been detected in tumor cells, including GBM cells. However, the intrinsic role of FOXP3 in GBM cells is poorly understood. Thus, we aimed to evaluate the effect of FOXP3 blockade in GBM. Meta-analysis of transcriptomic data indicated that FOXP3, which expression was higher in GBM biopsies than in normal brain, was associated with worse prognosis and chemo-resistance. It also correlated with the expression of markers of immune-suppression and epithelial-mesenchymal transition. Expression of FOXP3 in GBM cell lines and patient-derived cultures was upregulated by chemo- and radiotherapy, and its blockade using a cell penetrating peptide (P60) inhibited GBM cell migration, induced cytotoxicity and enhanced radio- and chemo-sensitivity. To improve the local availability of P60, we developed an adenoviral vector (Ad.P60) that enhanced the apoptotic response of GBM cells and reduced chemoresistance. Local treatment with Ad.P60 in mice bearing intracranial GBM reduced Treg infiltration, inhibited tumor growth and improved chemosensitivity to cisplatin, leading to long-term survival with combined chemo-gene therapy without generating neurotoxicity. Our results suggest that FOXP3 emerges as a dual-function molecule that could improve GBM response to standard treatment.
Insights
Blocking the transcription factor FOXP3 in glioblastoma (GBM) cells inhibits tumor growth and migration. This approach enhances GBM sensitivity to chemotherapy and radiotherapy, offering a promising therapeutic strategy for this aggressive brain cancer.
Area of Science:
- Neuro-oncology
- Cancer immunology
- Molecular biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis.
- The transcription factor FOXP3, typically associated with regulatory T cells, is found in GBM cells.
- The role of FOXP3 within GBM cells remains largely unclear, necessitating further investigation.
Purpose of the Study:
- To investigate the intrinsic role of FOXP3 in GBM.
- To evaluate the therapeutic potential of blocking FOXP3 in GBM.
- To assess the impact of FOXP3 blockade on GBM cell behavior and treatment response.
Main Methods:
- Meta-analysis of transcriptomic data to correlate FOXP3 expression with GBM prognosis and resistance.
- In vitro studies using GBM cell lines and patient-derived cultures to assess FOXP3 blockade effects (migration, cytotoxicity, radiosensitivity, chemosensitivity).
- Development of an adenoviral vector (Ad.P60) for targeted P60 delivery and in vivo studies in intracranial GBM mouse models.
Main Results:
- Elevated FOXP3 expression in GBM correlates with worse prognosis, chemo-resistance, immune suppression, and epithelial-mesenchymal transition.
- FOXP3 blockade via P60 peptide inhibited GBM cell migration, induced cytotoxicity, and enhanced sensitivity to chemo- and radiotherapy.
- Ad.P60 treatment reduced Treg infiltration, suppressed tumor growth, improved cisplatin chemosensitivity, and led to long-term survival in mice without neurotoxicity.
Conclusions:
- FOXP3 plays a dual role in GBM, influencing both tumor cell intrinsic properties and the tumor microenvironment.
- Targeting FOXP3 presents a novel therapeutic strategy to overcome GBM resistance and improve treatment outcomes.
- Combined chemo-gene therapy using Ad.P60 shows significant potential for treating glioblastoma.
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