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

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Regulation

Background:

• Tumor-associated macrophage (TAM) function is dictated by their metabolic state, influenced by the tumor microenvironment.
• Signals programming TAM metabolism are not fully understood, limiting therapeutic strategies.

Purpose of the Study:

• To investigate the role of NAMPT (NAD salvage synthesis enzyme) as a target of STAT1 in regulating TAM metabolism.
• To explore the impact of NAMPT activity on macrophage polarization and antitumor immunity.

Main Methods:

• Identified STAT1 binding to the Nampt-Regulatory Element-1 (NRE1) in the Nampt gene.
• Utilized genetic disruption of NRE1 and pharmacological NAMPT inhibition.
• Employed single-cell RNA sequencing (scRNAseq) in a novel NRE1-deficient mouse model of melanoma.

Main Results:

• STAT1-mediated regulation of NAMPT impacts M1 gene expression via glycolytic processes.
• NRE1 deficiency in myeloid and APC populations reduced Nampt and inflammatory gene expression.
• Targeted ablation of NRE1 in macrophages led to increased tumor burden in vivo.

Conclusions:

• IFNγ and STAT1 induce NAMPT, a key regulator of TAM metabolic programming and function.
• NAMPT activity is crucial for effective antitumor responses mediated by TAMs.
• Elevated NAMPT expression correlates with IFNγ response and improved melanoma patient survival.