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Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells

Author

Listed:
  • Sicheng Fu

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Kaixin He

    (University of Science and Technology of China)

  • Chenxi Tian

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Hua Sun

    (The First Affiliated Hospital of Anhui Medical University, Anhui Medical University)

  • Chenwen Zhu

    (The First Affiliated Hospital of Anhui Medical University, Anhui Medical University)

  • Shiyu Bai

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Jiwei Liu

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Qielan Wu

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Di Xie

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Ting Yue

    (University of Science and Technology of China)

  • Zhuxia Shen

    (Fudan University)

  • Qingqing Dai

    (The First Affiliated Hospital of Anhui Medical University)

  • Xiaojun Yu

    (The First Affiliated Hospital of Anhui Medical University)

  • Shu Zhu

    (University of Science and Technology of China)

  • Gang Liu

    (University of Science and Technology of China)

  • Rongbin Zhou

    (University of Science and Technology of China)

  • Shengzhong Duan

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology)

  • Zhigang Tian

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Tao Xu

    (Chinese Academy of Sciences)

  • Hua Wang

    (The First Affiliated Hospital of Anhui Medical University, Anhui Medical University)

  • Li Bai

    (University of Science and Technology of China
    University of Science and Technology of China)

Abstract

Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.

Suggested Citation

  • Sicheng Fu & Kaixin He & Chenxi Tian & Hua Sun & Chenwen Zhu & Shiyu Bai & Jiwei Liu & Qielan Wu & Di Xie & Ting Yue & Zhuxia Shen & Qingqing Dai & Xiaojun Yu & Shu Zhu & Gang Liu & Rongbin Zhou & She, 2020. "Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14332-x
    DOI: 10.1038/s41467-020-14332-x
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    Cited by:

    1. Chenxi Tian & Yu Wang & Miya Su & Yuanyuan Huang & Yuwei Zhang & Jiaxiang Dou & Changfeng Zhao & Yuting Cai & Jun Pan & Shiyu Bai & Qielan Wu & Sanwei Chen & Shuhang Li & Di Xie & Rong Lv & Yusheng Ch, 2024. "Motility and tumor infiltration are key aspects of invariant natural killer T cell anti-tumor function," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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