NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

J Clin Invest. 2017 Oct 2;127(10):3796-3809. doi: 10.1172/JCI91561. Epub 2017 Sep 11.


Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology*
  • Adenocarcinoma / pathology
  • Animals
  • Female
  • Growth Differentiation Factor 15 / genetics
  • Growth Differentiation Factor 15 / immunology*
  • Heterografts
  • Immunologic Surveillance*
  • MAP Kinase Kinase Kinases
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / immunology*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Neoplasm Transplantation
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Nitric Oxide / genetics
  • Nitric Oxide / immunology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology


  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • NF-kappa B
  • Neoplasm Proteins
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7