FOXO3-NF-κB RelA Protein Complexes Reduce Proinflammatory Cell Signaling and Function

Tumor-associated myeloid cells, including dendritic cells (DCs) and macrophages, are immune suppressive. This study demonstrates a novel mechanism involving FOXO3 and NF-kappa B RelA that controls myeloid cell signaling and impacts their immune-suppressive nature. We find that FOXO3 binds NF-kappa B RelA in the cytosol, impacting both proteins by preventing FOXO3 degradation and preventing NF-kappa B RelA nuclear translocation. The location of protein-protein interaction was determined to be near the FOXO3 transactivation domain. In turn, NF-kappa B RelA activation was restored upon deletion of the same sequence in FOXO3 containing the DNA binding domain. We have identified for the first time, to our knowledge, a direct protein-protein interaction between FOXO3 and NF-kappa B RelA in tumor-associated DCs. These detailed biochemical interactions provide the foundation for future studies to use the FOXO3-NF-kappa B RelA interaction as a target to enhance tumor-associated DC function to support or enhance antitumor immunity.