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PLoS One. 2014 Aug 11;9(8):e104230. doi: 10.1371/journal.pone.0104230. eCollection 2014.

Inhibition of CSF-1R supports T-cell mediated melanoma therapy.

Author information

1
Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
2
Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, the Netherlands.
3
Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
4
Plexxikon Inc., Berkeley, California, United States of America.

Abstract

Tumor associated macrophages (TAM) can promote angiogenesis, invasiveness and immunosuppression. The cytokine CSF-1 (or M-CSF) is an important factor of TAM recruitment and differentiation and several pharmacological agents targeting the CSF-1 receptor (CSF-1R) have been developed to regulate TAM in solid cancers. We show that the kinase inhibitor PLX3397 strongly dampened the systemic and local accumulation of macrophages driven by B16F10 melanomas, without affecting Gr-1(+) myeloid derived suppressor cells. Removal of intratumoral macrophages was remarkably efficient and a modest, but statistically significant, delay in melanoma outgrowth was observed. Importantly, CSF-1R inhibition strongly enhanced tumor control by immunotherapy using tumor-specific CD8 T cells. Elevated IFNγ production by T cells was observed in mice treated with the combination of PLX3397 and immunotherapy. These results support the combined use of CSF-1R inhibition with CD8 T cell immunotherapy, especially for macrophage-stimulating tumors.

PMID:
25110953
PMCID:
PMC4128661
DOI:
10.1371/journal.pone.0104230
[Indexed for MEDLINE]
Free PMC Article

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