NF-κB functions in tumor initiation by suppressing the surveillance of both innate and adaptive immune cells

Cell Rep. 2014 Oct 9;9(1):90-103. doi: 10.1016/j.celrep.2014.08.049. Epub 2014 Sep 25.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / immunology
  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology*
  • Cell Transformation, Neoplastic / pathology
  • Cytoskeletal Proteins
  • Immunity, Innate / immunology
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Mice, Transgenic
  • Microfilament Proteins
  • NF-kappa B / immunology*
  • Phosphoproteins / genetics
  • Phosphoproteins / immunology
  • Precancerous Conditions / immunology
  • Risk Factors
  • Signal Transduction
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology*
  • ras Proteins / biosynthesis
  • ras Proteins / genetics
  • ras Proteins / immunology

Substances

  • Cytoskeletal Proteins
  • Microfilament Proteins
  • NF-kappa B
  • Phosphoproteins
  • Transforming Growth Factor beta
  • Lcp1 protein, mouse
  • ras Proteins

Associated data

  • GEO/GSE59545