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

Abstract

Colony-stimulating factor 1 receptor (CSF1R) blockade abates tumor-associated macrophage (TAM) infiltrates and provides marked clinical benefits in diffuse-type tenosynovial giant cell tumors. However, facial edema is a common adverse event associated with TAM elimination in patients. In this study, we examined molecular and cellular events associated with edema formation in mice and human patients with cancer treated with a CSF1R blocking antibody. Extended antibody treatment of mice caused marked body weight gain, an indicator of enhanced body fluid retention. This was associated with an increase of extracellular matrix-remodeling metalloproteinases (MMPs), namely MMP2 and MMP3, and enhanced deposition of hyaluronan (HA) and proteoglycans, leading to skin thickening. Discontinuation of anti-CSF1R treatment or blockade of MMP activity restored unaltered body weight and normal skin morphology in the mice. In patients, edema developed at doses well below the established optimal biological dose for emactuzumab, a CSF1R dimerization inhibitor. Patients who developed edema in response to emactuzumab had elevated HA in peripheral blood. Our findings indicate that an early increase of peripheral HA can serve as a pharmacodynamic marker for edema development and suggest potential interventions based on MMP inhibition for relieving periorbital edema in patients treated with CSF1R inhibitors.

• Authors: Stefan Bissinger, Carina Hage, Vinona Wagner, Ilona-Petra Maser, Verena Brand, Martina Schmittnaegel, Anna-Maria Jegg, Michael Cannarile, Carl Watson, Irina Klaman, Natascha Rieder, Alejandra González Loyola, Tatiana V Petrova, Philippe A Cassier, Carlos Gomez-Roca, Vincent Sibaud, Michele De Palma, Sabine Hoves, Carola H Ries
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 598 (06 16 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 34135110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Antibodies, Monoclonal, Humanized
• CSF1R protein, human
• Proteoglycans
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
• emactuzumab
• Peptide Hydrolases

Topics

• Animals
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Edema
• Humans
• Macrophages
• Mice
• Neoplasms
• Peptide Hydrolases
• Proteoglycans
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (antagonists & inhibitors)