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

• Published in: Nature communications Vol. 12; no. 1; pp. 3530 - 17
• Main Authors: Wang, Yu-Chen, Wang, Xi, Yu, Jiaji, Ma, Feiyang, Li, Zhe, Zhou, Yang, Zeng, Samuel, Ma, Xiaoya, Li, Yan-Ruide, Neal, Adam, Huang, Jie, To, Angela, Clarke, Nicole, Memarzadeh, Sanaz, Pellegrini, Matteo, Yang, Lili
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-06-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/21; 13/31; 13/44; 13/51; 13/95; 14; 38/77; 38/90; 38/91; 42/109; 42/44; 631/67/1059/2325; 631/67/580; 64; 64/110; 64/60; 82/80; 82/83; 96; 96/95; Amine oxidase (flavin-containing); Animals; Brain; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Cancer; Cancer immunotherapy; Cell Line, Tumor; Data correlation; Drug Synergism; Enzymes; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Humanities and Social Sciences; Humans; Immunotherapy; Immunotherapy - methods; Kaplan-Meier Estimate; Lymphoma - genetics; Lymphoma - metabolism; Lymphoma - mortality; Macrophages; Melanoma - genetics; Melanoma - metabolism; Melanoma - mortality; Mice; Mice, Inbred C57BL; Mitochondria; Monoamine Oxidase - deficiency; Monoamine Oxidase - genetics; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - pharmacology; Monoamine Oxidase Inhibitors - therapeutic use; multidisciplinary; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - mortality; Neurological diseases; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - mortality; Oxidase; Oxidative stress; PD-1 protein; Polarization; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Reactive Oxygen Species - metabolism; RNA-Seq; Science; Science (multidisciplinary); Single-Cell Analysis; T-Lymphocytes - immunology; Tumor microenvironment; Tumor suppression; Tumor-Associated Macrophages - drug effects; Tumor-Associated Macrophages - metabolism; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23164-2

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.
Monoamine oxidase A (MAO-A) is an outer mitochondrial membrane-bound enzyme best known for its function in the brain, but also linked to cancer progression. Here, the authors show that MAO-A is expressed in tumor associated macrophages, promoting their immunosuppressive properties, and that MAO inhibition suppresses tumor growth in preclinical models.