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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / mortality
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Cell Line, Tumor
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Drug Synergism
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Immunotherapy / methods*
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Kaplan-Meier Estimate
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Lymphoma / genetics
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Lymphoma / metabolism
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Lymphoma / mortality
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Melanoma / genetics
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Melanoma / metabolism
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Melanoma / mortality
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Mice
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Mice, Inbred C57BL
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Monoamine Oxidase / deficiency
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Monoamine Oxidase / genetics
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Monoamine Oxidase / metabolism*
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Monoamine Oxidase Inhibitors / pharmacology*
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Monoamine Oxidase Inhibitors / therapeutic use
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Neoplasms / drug therapy*
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Neoplasms / genetics
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Neoplasms / immunology
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Neoplasms / mortality
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / mortality
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / metabolism
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RNA-Seq
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Reactive Oxygen Species / metabolism
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Single-Cell Analysis
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T-Lymphocytes / immunology
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Tumor-Associated Macrophages / drug effects*
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Tumor-Associated Macrophages / metabolism*
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Xenograft Model Antitumor Assays
Substances
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Monoamine Oxidase Inhibitors
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Reactive Oxygen Species
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Monoamine Oxidase