Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages

Rui Sun, Chao Lei, Zhishan Xu, Xuemei Gu, Liu Huang, Liang Chen, Yi Tan, Min Peng, Kavitha Yaddanapudi, Leah Siskind, Maiying Kong, Robert Mitchell, Jun Yan and Zhongbin Deng ()
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Rui Sun: University of Louisville
Chao Lei: University of Louisville
Zhishan Xu: University of Louisville
Xuemei Gu: University of Louisville
Liu Huang: Huazhong University of Science and Technology
Liang Chen: University of Louisville
Yi Tan: University of Louisville
Min Peng: Renmin Hospital of Wuhan University
Kavitha Yaddanapudi: University of Louisville
Leah Siskind: University of Louisville
Maiying Kong: University of Louisville
Robert Mitchell: University of Louisville
Jun Yan: University of Louisville
Zhongbin Deng: University of Louisville

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract The tumor microenvironment is reprogrammed by cancer cells and participates in all stages of tumor progression. Neutral ceramidase is a key regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of neutral ceramidase to the reprogramming of the tumor microenvironment is not well understood. Here, we find that deletion of neutral ceramidase in multiple breast cancer models in female mice accelerates tumor growth. Our result show that Ly6C+CD39+ tumor-infiltrating CD8 T cells are enriched in the tumor microenvironment and display an exhausted phenotype. Deletion of myeloid neutral ceramidase in vivo and in vitro induces exhaustion in tumor-infiltrating Ly6C+CD39+CD8+ T cells. Mechanistically, myeloid neutral ceramidase is required for the generation of lipid droplets and for the induction of lipolysis, which generate fatty acids for fatty-acid oxidation and orchestrate macrophage metabolism. Metabolite ceramide leads to reprogramming of macrophages toward immune suppressive TREM2+ tumor associated macrophages, which promote CD8 T cells exhaustion.

Date: 2024
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DOI: 10.1038/s41467-024-45084-7

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