CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Colony-stimulating factor 1 (CSF1) drives monocyte/macrophage survival and differentiation, supporting protumorigenic tumor-associated macrophages (TAMs).
• Targeting TAMs within the inflammatory tumor microenvironment is a promising strategy for sarcoma treatment.
• PLX3397 (pexidartinib) is a potent inhibitor of the CSF1 receptor (CSF1R), recently FDA-approved for tenosynovial giant cell tumor.

Purpose of the Study:

• To investigate the effects of PLX3397 on TAMs and sarcoma progression.
• To evaluate PLX3397's efficacy in preclinical sarcoma models.
• To explore PLX3397's impact on the tumor immune microenvironment.

Main Methods:

• Cytokine arrays to detect CSF1 in tumor-conditioned media (TCM).
• In vitro studies using bone marrow-derived macrophages (BMDMs) treated with CSF1, TCM, and PLX3397.
• In vivo studies using an osteosarcoma orthotopic xenograft model treated with PLX3397.
• Immunohistochemical analysis of tumor tissues to assess immune cell infiltration.

Main Results:

• CSF1 and other cytokines secreted by sarcoma cells promote M2 polarization, survival, and chemotaxis of BMDMs.
• PLX3397 inhibited CSF1/TCM-induced ERK1/2 phosphorylation, M2 polarization, survival, and chemotaxis in BMDMs.
• Systemic PLX3397 administration suppressed primary tumor growth, lung metastasis, and improved metastasis-free survival in osteosarcoma models.
• PLX3397 depleted TAMs and regulatory T cells, while enhancing CD8+ T cell infiltration in primary and metastatic tumors.

Conclusions:

• PLX3397 effectively modulates TAMs and T cells, demonstrating significant preclinical anti-sarcoma activity.
• Targeting CSF1R with PLX3397 offers a potential therapeutic strategy for bone and soft-tissue sarcomas.
• PLX3397's immunomodulatory effects suggest its utility in cancer immunotherapy.