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Published on: November 28, 2019
Polypharmacologic Reprogramming of Tumor-Associated Macrophages toward an Inflammatory Phenotype
Nao Nishida-Aoki1, Taranjit S Gujral2,3
1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Abstract:
Tumor-associated macrophages (TAM) are an important component of the tumor microenvironment (TME) that can promote tumor progression, metastasis, and resistance to therapies. Although TAMs represent a promising target for therapeutic intervention, the complexity of the TME has made the study of TAMs challenging. Here, we established a physiologically relevant in vitro TAM polarization system that recapitulates TAM protumoral activities. This system was used to characterize dynamic changes in gene expression and protein phosphorylation during TAM polarization and to screen phenotypic kinase inhibitors that impact TAM programming. BMS-794833, a multitargeted compound, was identified as a potent inhibitor of TAM polarization. BMS-794833 decreased protumoral properties of TAMs in vitro and suppressed tumor growth in mouse triple-negative breast cancer models. The effect of BMS-794833 was independent of its primary targets (MET and VEGFR2) but was dependent on its effect on multiple signaling pathways, including focal adhesion kinases, SRC family kinases, STAT3, and p38 MAPKs. Collectively, these findings underline the efficacy of polypharmacologic strategies in reprogramming complex signaling cascades activated during TAM polarization. SIGNIFICANCE: A physiologically relevant in vitro system of TAM polarization uncovers signaling pathways that regulate polarization and identifies strategies to target macrophage reprogramming to suppress cancer growth.
Insights
Tumor-associated macrophages (TAMs) promote cancer. A new in vitro system identified BMS-794833, a drug that inhibits TAM polarization and suppresses tumor growth by targeting multiple signaling pathways.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Tumor-associated macrophages (TAMs) are key players in the tumor microenvironment (TME), driving tumor progression, metastasis, and therapeutic resistance.
- Studying TAMs is challenging due to the complex TME, necessitating advanced in vitro models.
Purpose of the Study:
- To establish a physiologically relevant in vitro system for studying TAM polarization.
- To identify kinase inhibitors that can reprogram TAMs and inhibit their protumoral activities.
Main Methods:
- Developed an in vitro TAM polarization system mimicking protumoral TAM functions.
- Analyzed gene expression and protein phosphorylation during TAM polarization.
- Screened kinase inhibitors using the developed system.
Main Results:
- Identified BMS-794833, a multi-targeted compound, as a potent inhibitor of TAM polarization.
- BMS-794833 reduced protumoral TAM properties in vitro and suppressed tumor growth in triple-negative breast cancer mouse models.
- The drug's efficacy was linked to its impact on multiple signaling pathways, including focal adhesion kinases, SRC family kinases, STAT3, and p38 MAPKs, independent of its primary targets (MET, VEGFR2).
Conclusions:
- A novel in vitro TAM polarization system facilitates the study of signaling pathways regulating TAMs.
- Polypharmacology targeting multiple signaling pathways offers a promising strategy for reprogramming TAMs and inhibiting cancer growth.
