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

Abstract

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.

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

“…NAMPT has also been shown to be upregulated in tumor associated neutrophils (TANs) in patients with melanoma and head and neck cancer, and in murine cancer models. Inhibition of NAMPT in ex vivo TANs followed by adoptive transfer of the TANs into tumor-bearing mice reduced tumor angiogenesis and proliferation through suppression of SIRT1 and resultant transcriptional blockade of proangiogenic genes (143). While more studies are required to better understand the role NAMPT inhibition plays in the microenvironmental immune milieu, these and other preliminary reports suggest NAMPT inhibitors could be used to enhance immunotherapies in the clinic (144).…”

Neutrophil Diversity in Health and Disease

“…It is also not clear if N2 cells can change into N1 cells and vice versa under the influence of changes in the tumor microenvironment [9]. An interesting study in that regard recently described how nicotinamide phosphoribosyltransferase (NAMPT)part of the G-CSF signaling cascademight be involved in the protumorigenic conversion of neutrophils inside the tumor microenvironment by affecting angiogenesis [128]. In this study, inhibition of NAMPT signaling was shown to decrease the expression of the proangiogenic factors matrix metalloproteinase 9 (MMP-9), VEGF, and S100 calcium-binding protein A8 (S100A8) in TANs relative to control treatment, thus impairing the development of a functional tumor vasculature [128].…”

“…An interesting study in that regard recently described how nicotinamide phosphoribosyltransferase (NAMPT)part of the G-CSF signaling cascademight be involved in the protumorigenic conversion of neutrophils inside the tumor microenvironment by affecting angiogenesis [128]. In this study, inhibition of NAMPT signaling was shown to decrease the expression of the proangiogenic factors matrix metalloproteinase 9 (MMP-9), VEGF, and S100 calcium-binding protein A8 (S100A8) in TANs relative to control treatment, thus impairing the development of a functional tumor vasculature [128]. Moreover, recent work suggested that a glucose-restricted tumor microenvironment could induce metabolically adapted, oxidative neutrophils, and maintain intratumoral immunosuppression by a subpopulation of TANs [129].…”

Value of the preoperative prognostic nutritional index for the evaluation of patient prognosis after radical gastrectomy

“…Mantovani et al (20) showed that tumor-associated inflammation is characterized by the swelling of inflammatory cells and the production and release of inflammatory factors in tumor tissues. Inflammatory cells and immune cells, such as neutrophils, lymphocytes, and monocytes, in the peripheral blood of patients with tumor-associated inflammation are considered to be important factors leading to tumor development, invasion and metastasis (21)(22)(23)(24). Existing studies have shown that the NLR and LMR play important roles in determining the prognosis of cancer patients (25-27).…”