An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy

Nat Med. 2013 Sep;19(9):1114-23. doi: 10.1038/nm.3291. Epub 2013 Aug 4.


Although angiogenesis inhibitors have provided substantial clinical benefit as cancer therapeutics, their use is limited by resistance to their therapeutic effects. While ample evidence indicates that such resistance can be influenced by the tumor microenvironment, the underlying mechanisms remain incompletely understood. Here, we have uncovered a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance in multiple tumor models: lymphoma, lung and colon. Tumor-infiltrating T helper type 17 (T(H)17) cells and interleukin-17 (IL-17) induced the expression of granulocyte colony-stimulating factor (G-CSF) through nuclear factor κB (NF-κB) and extracellular-related kinase (ERK) signaling, leading to immature myeloid-cell mobilization and recruitment into the tumor microenvironment. The occurrence of T(H)17 cells and Bv8-positive granulocytes was also observed in clinical tumor specimens. Tumors resistant to treatment with antibodies to VEGF were rendered sensitive in IL-17 receptor (IL-17R)-knockout hosts deficient in T(H)17 effector function. Furthermore, pharmacological blockade of T(H)17 cell function sensitized resistant tumors to therapy with antibodies to VEGF. These findings indicate that IL-17 promotes tumor resistance to VEGF inhibition, suggesting that immunomodulatory strategies could improve the efficacy of anti-angiogenic therapy.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antibodies / immunology
  • CD11b Antigen / metabolism
  • Colorectal Neoplasms / metabolism
  • Drug Resistance, Neoplasm*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fibroblasts / metabolism
  • Gastrointestinal Hormones / metabolism
  • Granulocyte Colony-Stimulating Factor / biosynthesis
  • Granulocytes / metabolism
  • Humans
  • Interleukin-17 / metabolism*
  • Lung Neoplasms / metabolism
  • Lymphoma / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / immunology
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neovascularization, Pathologic / immunology*
  • Neuropeptides / metabolism
  • Paracrine Communication
  • Th17 Cells / immunology*
  • Tumor Microenvironment / immunology
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / immunology


  • Angiogenesis Inhibitors
  • Antibodies
  • CD11b Antigen
  • Gastrointestinal Hormones
  • Interleukin-17
  • NF-kappa B
  • Neuropeptides
  • Prok2 protein, mouse
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Granulocyte Colony-Stimulating Factor
  • Extracellular Signal-Regulated MAP Kinases