Targeting FOXP3 in glioblastoma: Blockade of tumor intrinsic effects boosts response to chemo-radiotherapy

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.

Keywords: Chemo-radioresistance; Diffuse gliomas; FOXP3; Gene therapy; Glioblastoma; Neuro-oncology.