Tumour expression of forkhead box protein P3 (FOXP3) and its exon 3-deleted isoform FOXP3Δ3 increases with tumour stage in patients with bladder cancer, according to new research published in Clinical Cancer Research. Furthermore, FOXP3Δ3-expressing cells show a specific gene signature that seems to confer chemotherapy resistance.

FOXP3 expression, initially described in the development of regulatory T cells, has been shown to be involved in epithelial differentiation of some cancer types, possibly contributing to disease aggressiveness. A team of researchers from the University of California Los Angeles, USA, examined expression of FOXP3 in bladder cancer specimens, finding increased levels in advanced-stage disease and an inverse correlation between FOXP3 expression and overall survival in patients who had undergone radical cystectomy.

Immunoblot and PCR experiments in samples from primary bladder tumours and five bladder cancer cell lines demonstrated that the FOXP3Δ3 isoform, rather than the full-length protein, was predominantly expressed in these tissues.

Investigating whether FOXP3Δ3 expression was inducing a more aggressive tumour cell phenotype, the team found increased spheroid formation and stem cell marker gene expression, and RNA sequencing demonstrated a unique gene expression signature in these cells. In addition, FOXP3Δ3-expressing cells formed larger tumours with features of high-grade carcinoma in vivo. In vitro, such cells showed resistance to cisplatin and gemcitabine treatment and preliminary results indicated a similar role of FOXP3 expression in chemotherapy-resistant patients.

The team validated their findings using data from the TCGA database and found increased expression of FOXP3 in TCGA-assigned tumour clusters II–IV and gene expression signatures that were unique for FOXP3Δ3-expressing cells.