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

Thomas B. Huffaker, H. Atakan Ekiz, Cindy Barba, Soh-Hyun Lee, Marah C. Runtsch, Morgan C. Nelson, Kaylyn M. Bauer, William W. Tang, Timothy L. Mosbruger, James E. Cox, June L. Round, Warren P. Voth () and Ryan M. O’Connell ()
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Thomas B. Huffaker: University of Utah
H. Atakan Ekiz: University of Utah
Cindy Barba: University of Utah
Soh-Hyun Lee: University of Utah
Marah C. Runtsch: University of Utah
Morgan C. Nelson: University of Utah
Kaylyn M. Bauer: University of Utah
William W. Tang: University of Utah
Timothy L. Mosbruger: University of Utah
James E. Cox: University of Utah
June L. Round: University of Utah
Warren P. Voth: University of Utah
Ryan M. O’Connell: University of Utah

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22923-5

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DOI: 10.1038/s41467-021-22923-5

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