Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis

Area of Science:

• Immunology
• Cancer Biology
• Cell Metabolism

Background:

• Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are key players in cancer development.
• The precise mechanisms controlling MDSC and TAM differentiation and function are not fully understood.

Purpose of the Study:

• To elucidate the role of Notch signaling in regulating myeloid cell development and function.
• To identify the molecular mechanisms linking lactate metabolism to MDSC and TAM phenotypes.

Main Methods:

• Investigated myeloid-specific Notch/RBP-J signaling activation in mouse models.
• Utilized liquid-chromatography-mass spectrometry (LC-MS) and CRISPR-Cas9 gene editing.
• Analyzed intracellular lactate levels and c-Jun protein stability.
• Examined clinical lung cancer patient samples.

Main Results:

• Myeloid-specific Notch activation downregulates lactate transporter MCT2 via Hes1, reducing intracellular lactate.
• Reduced lactate impairs granulocytic MDSC (G-MDSC) differentiation but promotes TAM maturation.
• Identified c-Jun as a lactate sensor, protected from degradation by lactate.
• Notch activation and blocked lactate import inhibit tumor progression by remodeling myeloid cells.
• The Notch-MCT2/lactate-c-Jun axis in myeloid cells correlates with tumorigenesis in lung cancer.

Conclusions:

• Lactate metabolism, regulated by Notch signaling, is a critical factor in MDSC differentiation and TAM maturation.
• Targeting the Notch-lactate-c-Jun axis in myeloid cells offers a potential strategy for cancer therapy.