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CSF-1/CSF-1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-Cell Infiltration in the Sarcoma Microenvironment.

Research paper by Tomohiro T Fujiwara, Mohamed A MA Yakoub, Andrew A Chandler, Alexander B AB Christ, Guangli G Yang, Ouathek O Ouerfelli, Vinagolu K VK Rajasekhar, Aki A Yoshida, Hiroya H Kondo, Toshiaki T Hata, Hiroshi H Tazawa, Yildirim Y Dogan, Malcolm A S MAS Moore, Toshiyoshi T Fujiwara, Toshifumi T Ozaki, et al.

Indexed on: 06 Jun '21Published on: 06 Jun '21Published in: Molecular cancer therapeutics



Abstract

Colony-stimulating factor 1 (CSF-1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the pro-tumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF-1 receptor (CSF-1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF-1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF-1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward a M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF-1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T cell-modulating effects that may translate into cancer immunotherapy for bone and soft tissue sarcomas. Copyright ©2021, American Association for Cancer Research.