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Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer

Author

Listed:
  • Kai Zhang

    (Shanghai Jiao Tong University School of Medicine)

  • Kaiyuan Liu

    (Shanghai Jiao Tong University School of Medicine)

  • Benxia Hu

    (Chinese Academy of Sciences)

  • Genyu Du

    (Shanghai Jiao Tong University School of Medicine)

  • Xinyu Chen

    (Shanghai Jiao Tong University School of Medicine)

  • Lingling Xiao

    (Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine)

  • Yingchao Zhang

    (Shanghai Jiao Tong University School of Medicine)

  • Luyao Jiang

    (Shanghai Jiao Tong University School of Medicine)

  • Na Jing

    (Shanghai Jiao Tong University School of Medicine)

  • Chaping Cheng

    (Shanghai Jiao Tong University School of Medicine)

  • Jinming Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Penghui Xu

    (Shanghai Jiao Tong University School of Medicine)

  • You Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Pengfei Ma

    (Shanghai Jiao Tong University School of Medicine)

  • Guanglei Zhuang

    (Shanghai Jiao Tong University School of Medicine)

  • Huifang Zhao

    (Shanghai Jiao Tong University School of Medicine)

  • Yujiao Sun

    (Shanghai Jiao Tong University School of Medicine)

  • Deng Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Qi Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Wei Xue

    (Shanghai Jiao Tong University School of Medicine)

  • Wei-Qiang Gao

    (Shanghai Jiao Tong University School of Medicine)

  • Pengcheng Zhang

    (Shanghai Tech University)

  • Helen He Zhu

    (Shanghai Jiao Tong University School of Medicine)

Abstract

Iron is an essential biomineral in the human body. Here, we describe a subset of iron-loaded cancer-associated fibroblasts, termed as FerroCAFs, that utilize iron to induce immunosuppression in prostate cancer and predict an unfavorable clinical outcome. FerroCAFs secrete myeloid cell-associated proteins, including CCL2, CSF1 and CXCL1, to recruit immunosuppressive myeloid cells. We report the presence of FerroCAFs in prostate cancer from both mice and human, as well as in human lung and ovarian cancers, and identify a conserved cell surface marker, the poliovirus receptor. Mechanistically, the accumulated iron in FerroCAFs is caused by Hmox1-mediated iron release from heme degradation. The intracellular iron activates the Kdm6b, an iron-dependent epigenetic enzyme, to induce an accessible chromatin state and transcription of myeloid cell-associated protein genes. Targeting the FerroCAFs by inhibiting the Hmox1/iron/Kdm6b signaling axis incurs anti-tumor immunity and tumor suppression. Collectively, we report an iron-loaded FerroCAF cluster that drives immunosuppression through an iron-dependent epigenetic reprogramming mechanism and reveal promising therapeutic targets to boost anti-tumor immunity.

Suggested Citation

  • Kai Zhang & Kaiyuan Liu & Benxia Hu & Genyu Du & Xinyu Chen & Lingling Xiao & Yingchao Zhang & Luyao Jiang & Na Jing & Chaping Cheng & Jinming Wang & Penghui Xu & You Wang & Pengfei Ma & Guanglei Zhua, 2024. "Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53233-1
    DOI: 10.1038/s41467-024-53233-1
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    3. Suoqin Jin & Christian F. Guerrero-Juarez & Lihua Zhang & Ivan Chang & Raul Ramos & Chen-Hsiang Kuan & Peggy Myung & Maksim V. Plikus & Qing Nie, 2021. "Inference and analysis of cell-cell communication using CellChat," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
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