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.
Highlights
Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy
In addition to changes in classical genes involved in regulating macrophage immune responses, we observed the induction of a Maoa gene in TAMs (Fig. 1a), suggesting that Monoamine oxidase A (MAO-A) may be involved in modulating TAM activities
A degree of Maoa expression leakage in the brain had been previously reported in these mice[33], analysis of their immune system showed nearly complete ablation of MAOA expression in major lymphoid organs, including the spleen and bone marrow (BM) (Supplementary Fig. 1a)
Summary
Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. 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. Growing evidence suggests that TAMs are responsible for inhibiting antitumor T-cell reactivity and limiting the ICB therapy efficacy, making TAMs potential targets for reversing the immunosuppressive TME and improving cancer immunotherapy[10,11,12]. A binary polarization system is commonly used in macrophage studies, in most large-scale transcriptome analyses, TAMs showed a continuum of phenotypes expressing both immunostimulatory and immunosuppressive markers in addition to the extreme ends of polarization[16,17] These mixed phenotypes and polarization states suggest the complexity of the TME and the residential TAM functionality. PD-L1 and PD-L2 expressed on TAMs interact with
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