Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression

Area of Science:

• Oncology
• Immunology
• Neuroscience

Background:

• Perineural invasion (PNI) is a significant predictor of poor patient outcomes in various cancers.
• The tumor microenvironment's role in facilitating PNI, particularly the involvement of peripheral nerves and immune cells, remains incompletely understood.

Purpose of the Study:

• To elucidate the mechanisms by which inflammatory monocytes (IM) contribute to PNI.
• To identify key molecular signaling pathways involved in IM recruitment and function during PNI.

Main Methods:

• Utilized adoptive transfer experiments with genetically engineered mouse models.
• Investigated the roles of CCL2, CCR2, and cathepsin B in PNI.
• Performed correlative studies on human cancer specimens.

Main Results:

• CCR2-expressing IM are recruited to sites of PNI and differentiate into macrophages.
• Schwann cell-derived CCL2 drives IM recruitment via CCR2 signaling, potentiating nerve invasion through cathepsin B.
• Inhibition of CCL2-CCR2 signaling or cathepsin B significantly reduced PNI in vivo.
• Cathepsin B-producing macrophages were found in nerves of human specimens with PNI, correlating with increased local tumor recurrence.

Conclusions:

• PNI involves the corruption of nerve repair pathways by cancer cells and inflammatory monocytes.
• Targeting IM recruitment (CCL2-CCR2 axis) and function (cathepsin B) presents a potential therapeutic strategy for PNI.