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

Research paper by Ekaterina E Pylaeva, Mozhgan Dehghan MD Harati, Ilona I Spyra, Sharareh S Bordbari, Sarah S Strachan, Basant Kumar BK Thakur, Benedikt B Höing, Cindy C Franklin, Julia J Skokowa, Karl K Welte, Dirk D Schadendorf, Agnes A Bankfalvi, Sven S Brandau, Stephan S Lang, Jadwiga J Jablonska

Indexed on: 20 Aug '18Published on: 20 Aug '18Published in: International Journal of Cancer



Abstract

Tumor-associated neutrophils 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 tumor-associated neutrophils 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 tumor-associated neutrophils 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. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.