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Summary: NF-κB is considered a major contributor to tumor development, but how this factor functions in the initial stages of oncogenesis is not clear. In a model of Ras-induced transformation, we probed NF-κB function as preneoplastic cells formed tumors in mice. As previously shown, the p65 subunit of NF-κB acts as a tumor suppressor in normal cells by sustaining senescence following DNA damage. Our current data reveal that, following immortalization, p65 switches to an oncogene by counteracting the surveillance properties of immune cells. NF-κB exerts this effect by protecting transformed cells against macrophage-derived proapoptotic factors, tumor necrosis factor, and nitric oxide. Additionally, NF-κB acts through transforming growth factor beta (TGF-β) to mitigate T cell cytotoxicity and other factors to expand myeloid-derived suppressor cells. Together, these data suggest that NF-κB functions in the early stages of transformation by suppressing immune surveillance of both innate and adaptive immune cells, information that may be useful for targeted immunotherapies. : NF-κB in cellular transformation is well documented, but how NF-κB contributes to the initial stages of tumorigenesis is not clear. Here, Wang et al. show that in preneoplastic cells, the RelA/p65 subunit of NF-κB functions as a tumor suppressor by maintaining cells in a senescent state through the regulation of DNA repair. However in Ras-expressing cells undergoing transformation, RelA/p65 switches to an oncogene by protecting tumor cells from being eliminated by immune surveillance. These results have implications for targeted anticancer immunotherapy. |
