A Stat1 bound enhancer promotes Nampt expression and function within tumor associated macrophages

Abstract

Tumor associated macrophage responses are regulated by distinct metabolic states that affect their function. However, the ability of specific signals in the local tumor microenvironment to program macrophage metabolism remains under investigation. Here, we identify NAMPT, the rate limiting enzyme in NAD salvage synthesis, as a target of STAT1 during cellular activation by interferon gamma, an important driver of macrophage polarization and antitumor responses. We demonstrate that STAT1 occupies a conserved element within the first intron of Nampt, termed Nampt-Regulatory Element-1 (NRE1). Through disruption of NRE1 or pharmacological inhibition, a subset of M1 genes is sensitive to NAMPT activity through its impact on glycolytic processes. scRNAseq is used to profile in vivo responses by NRE1-deficient, tumor-associated leukocytes in melanoma tumors through the creation of a unique mouse strain. Reduced Nampt and inflammatory gene expression are present in specific myeloid and APC populations; moreover, targeted ablation of NRE1 in macrophage lineages results in greater tumor burden. Finally, elevated NAMPT expression correlates with IFNγ responses and melanoma patient survival. This study identifies IFN and STAT1-inducible Nampt as an important factor that shapes the metabolic program and function of tumor associated macrophages.

Extracellular nicotinamide phosphoribosyltransferase boosts IFNγ-induced macrophage polarization independently of TLR4

“…Our RNAseq analysis shows that the Nampt is one of the most IFNg-upregulated genes (Figure 2D; log2 fold-change of 2.1 over control) and is strikingly further potentiated by the co-stimulation of PECs with eN-AMPT (log2 fold-change of 2.75 over control). Accordingly, it has been recently reported that IFNg upregulates iNAMPT expression in a STAT-dependent manner (Huffaker et al, 2021). We confirmed RNAseq results by qPCR analysis.…”

“…There is abundant literature regarding NAMPT and macrophages. Huffaker et al have highlighted the role of intracellular NAMPT (iNAMPT) in mediating the effects of IFNg in tumor-associated macrophages (Huffaker et al, 2021). Such observations prevented us from using specific inhibitors of this enzyme, as they would have had a confounding effect.…”

A Nicotinamide Phosphoribosyltransferase Inhibitor, FK866, Suppresses the Growth of Anaplastic Meningiomas and Inhibits Immune Checkpoint Expression by Regulating STAT1

“…Intriguingly, a novel study revealed that STAT1 occupies a conserved element within the first intron of NAMPT. By binding this site, STAT1 can promote NAMPT expression in tumor-associated macrophages ( 45 ). It seems that there is a positive feedback mechanism involving STAT1 and NAMPT.…”

Shaping Polarization Of Tumor-Associated Macrophages In Cancer Immunotherapy

“…Both the JAK/STAT1 and JAK/STAT3 signaling pathways participate in macrophage polarization. The JAK/STAT1 signaling pathway can be activated by IFN-γ, which in turn upregulates the expression of nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting enzyme for NAD salvage synthesis ( 35 ). This study demonstrated that STAT1-induced NAMPT drives glycolysis, M1 polarization, and better outcomes in both mouse and human models of melanoma, while inhibition of NAMPT with FK866 reverses these effects.…”