CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment

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  • Tomohiro Fujiwara
    1Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Mohamed A. Yakoub
    1Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Andrew Chandler
    1Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Alexander B. Christ
    1Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Guangli Yang
    4Organic Synthesis Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Ouathek Ouerfelli
    4Organic Synthesis Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Vinagolu K. Rajasekhar
    1Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Aki Yoshida
    3Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
  • Hiroya Kondo
    3Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
  • Toshiaki Hata
    3Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
  • Hiroshi Tazawa
    5Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
  • Yildirim Dogan
    6Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Malcolm A.S. Moore
    6Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Toshiyoshi Fujiwara
    5Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
  • Toshifumi Ozaki
    3Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
  • Ed Purdue
    2Hospital for Special Surgery, New York, New York.
  • John H. Healey
    1Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York.

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<jats:title>Abstract</jats:title> <jats:p>Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic 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 CSF1 receptor (CSF1R). 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 CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow–derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 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.</jats:p>

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