1261) now find that these impotent cells can be reverted into weapons of tumor destruction by simply suppressing a kinase.
Macrophages can destroy tumor cells by producing inflammatory molecules. But macrophages within tumors often secrete harmless antiinflammatory cytokines and proteins that promote tumor growth. Tumor cells induce this transformation, but the signals that drive the conversion were unknown.
Hagemann et al. now find that tumor macrophages in mice are disarmed by signals that activate NF-κB—a transcription factor that normally drives inflammation. As in inflammation, tumor macrophage NF-κB was turned on by IκB kinase (IKK) β. In tumors, however, IKKβ also suppressed STAT1—a transcription factor that turns on tumor-fighting genes. The basis for this difference is unclear. Perhaps the tumor contains unique cues that instruct the IKK pathway to shut off STAT1.
STAT1 suppression in macrophages depended solely on the cytokine receptor IL-1R and its downstream adaptor, MyD88, suggesting that tumors might protect themselves by secreting the IL-1R ligand, IL-1β. Macrophages from tumors or from healthy animals became in vivo tumor killers when engineered to express dominant-negative IKKβ. These reprogrammed macrophages produced high levels of IL-12, which recruited tumor-fighting NK cells. The group is now investigating whether infusing similarly reprogramed macrophages into cancer patients will help reverse tumor growth.