Role of Forkhead Box P3 in Interferon g-mediated PD-L1 Expression and Bladder Cancer Differentiation

Antagonism of the PD-1/PD-L1 axis is a critical therapeutic strategy for advanced bladder cancer patients. IFNg functions as a key regulator of PD-L1 in both immune as well as cancer cells. Forkhead Box P3 (FOXP3) is a transcription factor synonymous in T regulatory cell function, but with increasingly described functions in cancer cells. Here we investigated the relationship between FOXP3 and PD-L1 in bladder cancer. We showed that FOXP3 is critical in the ability for IFNg to activate PD-L1 in bladder cancer cells. FOXP3 can bind to the PD-L1 promoter and induces a gene program that leads to regulation of multiple immune-related genes and genes involved in epithelial-to-mesenchymal transition. Using in vitro and in vivo human and murine models, we showed that FOXP3 can regulate bladder cancer differentiation as well as promote metastases. Furthermore, FOXP3 may be a convergent factor for multiple activators of PD-L1 including by cisplatin.