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

Author

Listed:
  • Rui Sun

    (University of Louisville
    University of Louisville
    Renmin Hospital of Wuhan University)

  • Chao Lei

    (University of Louisville
    University of Louisville)

  • Zhishan Xu

    (University of Louisville
    University of Louisville)

  • Xuemei Gu

    (University of Louisville)

  • Liu Huang

    (Huazhong University of Science and Technology)

  • Liang Chen

    (University of Louisville
    University of Louisville)

  • Yi Tan

    (University of Louisville)

  • Min Peng

    (Renmin Hospital of Wuhan University)

  • Kavitha Yaddanapudi

    (University of Louisville
    University of Louisville)

  • Leah Siskind

    (University of Louisville)

  • Maiying Kong

    (University of Louisville
    University of Louisville)

  • Robert Mitchell

    (University of Louisville
    University of Louisville)

  • Jun Yan

    (University of Louisville
    University of Louisville)

  • Zhongbin Deng

    (University of Louisville
    University of Louisville)

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.

Suggested Citation

  • 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 & Zhongbin Deng, 2024. "Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45084-7
    DOI: 10.1038/s41467-024-45084-7
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    References listed on IDEAS

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    1. Andrew C. Scott & Friederike Dündar & Paul Zumbo & Smita S. Chandran & Christopher A. Klebanoff & Mojdeh Shakiba & Prerak Trivedi & Laura Menocal & Heather Appleby & Steven Camara & Dmitriy Zamarin & , 2019. "TOX is a critical regulator of tumour-specific T cell differentiation," Nature, Nature, vol. 571(7764), pages 270-274, July.
    2. Omar Khan & Josephine R. Giles & Sierra McDonald & Sasikanth Manne & Shin Foong Ngiow & Kunal P. Patel & Michael T. Werner & Alexander C. Huang & Katherine A. Alexander & Jennifer E. Wu & John Attanas, 2019. "TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion," Nature, Nature, vol. 571(7764), pages 211-218, July.
    3. Thomas Duhen & Rebekka Duhen & Ryan Montler & Jake Moses & Tarsem Moudgil & Noel F. de Miranda & Cheri P. Goodall & Tiffany C. Blair & Bernard A. Fox & Jason E. McDermott & Shu-Ching Chang & Gary Grun, 2018. "Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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