NAMPT signaling is critical for the proangiogenic activity of tumor-associated neutrophils

Int J Cancer. 2019 Jan 1;144(1):136-149. doi: 10.1002/ijc.31808. Epub 2018 Oct 30.


Tumor-associated neutrophils (TANs) regulate many processes associated with tumor progression, and depending on the microenvironment, they can exhibit pro- or antitumor functions. However, the molecular mechanisms regulating their tumorigenicity are not clear. Using transplantable tumor models, we showed here that nicotinamide phosphoribosyltransferase (NAMPT), a molecule involved in CSF3R downstream signaling, is essential for tumorigenic conversion of TANs and their pro-angiogenic switch. As a result tumor vascularization and growth are strongly supported by these cells. Inhibition of NAMPT in TANs leads to their antitumor conversion. Adoptive transfer of such TANs into B16F10-tumor bearing mice attenuates tumor angiogenesis and growth. Of note, we observe that the regulation of NAMPT signaling in TANs, and its effect on the neutrophil tumorigenicity, are analogous in mice and human. NAMPT is up-regulated in TANs from melanoma and head-and-neck tumor patients, and its expression positively correlates with tumor stage. Mechanistically, we found that targeting of NAMPT suppresses neutrophil tumorigenicity by inhibiting SIRT1 signaling, thereby blocking transcription of pro-angiogenic genes. Based on these results, we propose that NAMPT regulatory axis is important for neutrophils to activate angiogenic switch during early stages of tumorigenesis. Thus, identification of NAMPT as the critical molecule priming protumor functions of neutrophils provides not only mechanistic insight into the regulation of neutrophil tumorigenicity, but also identifies a potential pathway that may be targeted therapeutically in neutrophils. This, in turn, may be utilized as a novel mode of cancer immunotherapy.

Keywords: NAMPT; angiogenesis; neutrophil polarization; tumor-associated neutrophils.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology
  • Adoptive Transfer
  • Adult
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Neoplasms / blood supply
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Neutrophils / transplantation
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors
  • Nicotinamide Phosphoribosyltransferase / genetics
  • Nicotinamide Phosphoribosyltransferase / metabolism*
  • Piperidines / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tumor Burden / drug effects
  • Tumor Burden / genetics


  • Acrylamides
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Piperidines
  • Nicotinamide Phosphoribosyltransferase