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Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy

Author

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  • Yu-Chen Wang

    (Immunology and Molecular Genetics, University of California)

  • Xi Wang

    (Immunology and Molecular Genetics, University of California)

  • Jiaji Yu

    (Immunology and Molecular Genetics, University of California)

  • Feiyang Ma

    (University of California)

  • Zhe Li

    (Immunology and Molecular Genetics, University of California)

  • Yang Zhou

    (Immunology and Molecular Genetics, University of California)

  • Samuel Zeng

    (Immunology and Molecular Genetics, University of California)

  • Xiaoya Ma

    (Immunology and Molecular Genetics, University of California)

  • Yan-Ruide Li

    (Immunology and Molecular Genetics, University of California)

  • Adam Neal

    (University of California
    University of California Los Angeles)

  • Jie Huang

    (Immunology and Molecular Genetics, University of California)

  • Angela To

    (Immunology and Molecular Genetics, University of California)

  • Nicole Clarke

    (Immunology and Molecular Genetics, University of California)

  • Sanaz Memarzadeh

    (University of California
    University of California Los Angeles
    The VA Greater Los Angeles Healthcare System
    University of California)

  • Matteo Pellegrini

    (University of California)

  • Lili Yang

    (Immunology and Molecular Genetics, University of California
    University of California
    University of California
    University of California)

Abstract

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.

Suggested Citation

  • Yu-Chen Wang & Xi Wang & Jiaji Yu & Feiyang Ma & Zhe Li & Yang Zhou & Samuel Zeng & Xiaoya Ma & Yan-Ruide Li & Adam Neal & Jie Huang & Angela To & Nicole Clarke & Sanaz Memarzadeh & Matteo Pellegrini , 2021. "Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23164-2
    DOI: 10.1038/s41467-021-23164-2
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