PMID- 34088832
OWN - NLM
STAT- MEDLINE
DCOM- 20220217
LR  - 20220802
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 20
IP  - 8
DP  - 2021 Aug
TI  - CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated 
      Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment.
PG  - 1388-1399
LID - 10.1158/1535-7163.MCT-20-0591 [doi]
AB  - 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.
CI  - (c)2021 American Association for Cancer Research.
FAU - Fujiwara, Tomohiro
AU  - Fujiwara T
AD  - Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer 
      Center, New York, New York.
AD  - Hospital for Special Surgery, New York, New York.
AD  - Department of Orthopaedic Surgery, Okayama University Graduate School of 
      Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
FAU - Yakoub, Mohamed A
AU  - Yakoub MA
AD  - Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer 
      Center, New York, New York.
AD  - Hospital for Special Surgery, New York, New York.
FAU - Chandler, Andrew
AU  - Chandler A
AUID- ORCID: 0000-0002-2527-0125
AD  - Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer 
      Center, New York, New York.
AD  - Hospital for Special Surgery, New York, New York.
FAU - Christ, Alexander B
AU  - Christ AB
AUID- ORCID: 0000-0002-0447-5762
AD  - Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer 
      Center, New York, New York.
AD  - Hospital for Special Surgery, New York, New York.
FAU - Yang, Guangli
AU  - Yang G
AD  - Organic Synthesis Core Laboratory, Memorial Sloan Kettering Cancer Center, New 
      York, New York.
FAU - Ouerfelli, Ouathek
AU  - Ouerfelli O
AUID- ORCID: 0000-0002-7038-0219
AD  - Organic Synthesis Core Laboratory, Memorial Sloan Kettering Cancer Center, New 
      York, New York.
FAU - Rajasekhar, Vinagolu K
AU  - Rajasekhar VK
AD  - Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer 
      Center, New York, New York.
FAU - Yoshida, Aki
AU  - Yoshida A
AD  - Department of Orthopaedic Surgery, Okayama University Graduate School of 
      Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
FAU - Kondo, Hiroya
AU  - Kondo H
AD  - Department of Orthopaedic Surgery, Okayama University Graduate School of 
      Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
FAU - Hata, Toshiaki
AU  - Hata T
AD  - Department of Orthopaedic Surgery, Okayama University Graduate School of 
      Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
FAU - Tazawa, Hiroshi
AU  - Tazawa H
AUID- ORCID: 0000-0003-4658-1050
AD  - Department of Gastroenterological Surgery, Okayama University Graduate School of 
      Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
FAU - Dogan, Yildirim
AU  - Dogan Y
AD  - Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - AVROBIO Inc., One Kendall Square, Cambridge, Massachusetts.
FAU - Moore, Malcolm A S
AU  - Moore MAS
AD  - Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Fujiwara, Toshiyoshi
AU  - Fujiwara T
AD  - Department of Gastroenterological Surgery, Okayama University Graduate School of 
      Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
FAU - Ozaki, Toshifumi
AU  - Ozaki T
AD  - Department of Orthopaedic Surgery, Okayama University Graduate School of 
      Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
FAU - Purdue, Ed
AU  - Purdue E
AD  - Hospital for Special Surgery, New York, New York.
FAU - Healey, John H
AU  - Healey JH
AUID- ORCID: 0000-0002-0802-1186
AD  - Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer 
      Center, New York, New York. healeyj@mskcc.org.
AD  - Hospital for Special Surgery, New York, New York.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - R50 CA243895/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210604
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Aminopyridines)
RN  - 0 (CSF1 protein, human)
RN  - 0 (CSF1R protein, human)
RN  - 0 (Pyrroles)
RN  - 0 (Receptors, Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - 6783M2LV5X (pexidartinib)
RN  - 81627-83-0 (Macrophage Colony-Stimulating Factor)
SB  - IM
MH  - Aminopyridines/*pharmacology
MH  - Animals
MH  - Apoptosis
MH  - Bone Neoplasms/drug therapy/immunology/metabolism/pathology
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Cell Proliferation
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Lung Neoplasms/drug therapy/immunology/metabolism/secondary
MH  - Lymphocytes, Tumor-Infiltrating/*immunology
MH  - Macrophage Colony-Stimulating Factor/*antagonists & inhibitors
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Osteosarcoma/drug therapy/*immunology/metabolism/pathology
MH  - Pyrroles/*pharmacology
MH  - Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/*antagonists & 
      inhibitors
MH  - Tumor Cells, Cultured
MH  - *Tumor Microenvironment
MH  - Tumor-Associated Macrophages/*immunology
MH  - Xenograft Model Antitumor Assays
PMC - PMC9336538
MID - NIHMS1815485
COIS- CONFLICT OF INTEREST The authors TF, MY, AC1 AC2, GY, OO, RV, TO, EP disclosed no 
      potential conflicts relevant to this article. JH is a paid consultant for Daiichi 
      Sankyo.
EDAT- 2021/06/06 06:00
MHDA- 2022/02/19 06:00
PMCR- 2022/08/01
CRDT- 2021/06/05 05:36
PHST- 2020/07/20 00:00 [received]
PHST- 2021/03/10 00:00 [revised]
PHST- 2021/05/25 00:00 [accepted]
PHST- 2021/06/06 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2021/06/05 05:36 [entrez]
PHST- 2022/08/01 00:00 [pmc-release]
AID - 1535-7163.MCT-20-0591 [pii]
AID - 10.1158/1535-7163.MCT-20-0591 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2021 Aug;20(8):1388-1399. doi: 10.1158/1535-7163.MCT-20-0591. 
      Epub 2021 Jun 4.