SUMMARY
Monoamine oxidase A (MAO-A) is postulated to play a critical role in regulating tumor associated macrophages (TAMs) polarization and TAM-induced/dependent immune response. Inhibition of MAO-A serves as a novel therapeutic target to prevent TAM polarization and -induce a robust antitumor immune response.
BACKGROUND
TAMs are prominent metastasis promoters within the tumor microenvironment (TME). They do so by modulating tumor growth, tumor angiogenesis, immune regulation, metastasis, and chemoresistance. TAMs can be divided into M1 (classical-activated macrophages) and M2 (alternative-activated macrophages) phenotype: M1 macrophage play an important role in the innate responses in pathogen invading and anti-tumor activity, while M2 macrophage are anti-inflammatory and can promote tumor growth.
Within the TME, macrophages can be polarized toward an immune-stimulatory phenotype by pro- inflammatory factors (e.g., Interferon-gamma (IFN-γ)) or toward an immune-suppressive phenotype by anti- inflammatory factors (e.g., Interleukin 4 (IL–4) and Interleukin (IL–13)). As a tumor develops and progresses, the secretion of IL–4 and IL–13 produced by tumor cells and CD4+ T cells within the TME results in the polarization of TAMs i.e., M1 M2, an immunosuppressive phenotype thereby, promoting tumor growth, malignancy, and metastasis. Thus, reprogramming TAMs is an attractive immunotherapy strategy.
MAOA is an enzyme found within the outer mitochondrial membrane encoded by the X-linked MAOA gene. MOA-A is a key homeostatic regulator of monoamine neurotransmitters such as serotonin, dopamine, epinephrine, and norepinephrine - pivotal for normal brain function. By the way of regulating neurotransmitters, MAOA modulates neuronal activities, behavior and moods. MAOA is implicated in a wide range of neuropsychiatric disorders including depression and Parkinson’s Disease (PD). Several kinds of MAOA inhibitors are approved by the FDA for neuropsychiatric and neurodegenerative diseases. However, the role of MAO-A outside the brain especially, how MAO-A regulates macrophage activity and anti-tumor immune response remains elusive and vague.
INNOVATION
Dr. Lili Yang and colleagues in the Department of Microbiology, Immunology, and Molecular Genetics at UCLA have discovered that MAOA as a critical regulator of TAM within the TME. Genetic ablation of MAOA gene can inhibit TAM M2 polarization and can promote antitumor immunity. In addition, MAOA inhibitors were shown robust antitumor efficacy in vitro and in vivo. By combining these inhibitors with PD-1/PD-L1 blockade result in synergistic tumor suppression efficacy, suggesting that MAOA inhibition can be a valuable treatment for single or combination cancer immunotherapies.
POTENTIAL APPLICATIONS:
- Cancer immunotherapy (standalone or in combination with immune checkpoint inhibitors such as PD-L1)
- Dual therapy benefits to cancer patients i.e., anti-depression and anti-tumor activity of MAOAI
ADVANTAGES:
- Novel drug target with no serious side effects
- Synergistic tumor suppression with PD-1/PD-L1 inhibitors
- Multiple MAOA inhibitors already approved by FDA
STATE OF DEVELOPMENT:
MAOA inhibitors have shown promising results in preclinical mouse tumor models. Combination of MAOA inhibitors with PD-1/PD-L1 inhibitors showed synergistic tumor suppression. Both results suggest MAOA is a potential drug target of cancer immunotherapy.
Related Papers (from the inventors only)
- Wang, Xi, et al. “Targeting Monoamine Oxidase A for T Cell–Based Cancer Immunotherapy.” Science Immunology, vol. 6, no. 59, 2021, p. eabh2383, doi:10.1126/sciimmunol.abh2383.
- Wang, Yu-Chen, et al. “Targeting Monoamine Oxidase A-Regulated Tumor-Associated Macrophage Polarization for Cancer Immunotherapy.” Nature Communications, vol. 12, no. 1, Springer US, 2021, pp. 1–17, doi:10.1038/s41467-021-23164-2.