Macrophage depletion induces edema through release of matrix-degrading proteases and proteoglycan deposition

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Colony-stimulating factor 1 receptor (CSF1R) blockade effectively reduces tumor-associated macrophages (TAMs) and benefits patients with diffuse-type tenosynovial giant cell tumors.
• Facial edema is a frequent adverse event linked to TAM elimination during CSF1R inhibitor therapy.

Purpose of the Study:

• To investigate the molecular and cellular mechanisms underlying edema formation in mice and human cancer patients treated with a CSF1R blocking antibody.
• To identify potential biomarkers and therapeutic strategies for managing edema associated with CSF1R inhibition.

Main Methods:

• Mice treated with a CSF1R blocking antibody were monitored for body weight changes and skin morphology.
• Extracellular matrix components, including metalloproteinases (MMPs), hyaluronan (HA), and proteoglycans, were analyzed in mouse tissues.
• Human patients receiving emactuzumab (a CSF1R inhibitor) were assessed for edema development and peripheral HA levels.

Main Results:

• Extended CSF1R blockade in mice led to significant body weight gain, indicating fluid retention.
• Increased MMP2, MMP3, HA, and proteoglycan deposition resulted in skin thickening in treated mice.
• Edema in patients occurred at sub-optimal emactuzumab doses, with elevated peripheral HA correlating with edema development.

Conclusions:

• CSF1R blockade-induced edema is associated with increased extracellular matrix remodeling, specifically elevated hyaluronan and MMP activity.
• Peripheral hyaluronan increase can serve as an early pharmacodynamic marker for edema.
• MMP inhibition presents a potential therapeutic approach to mitigate periorbital edema in patients receiving CSF1R inhibitors.