title: Inhibition of CSF-1R supports T-cell mediated melanoma therapy.
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.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Sluijter
authors.affiliation: Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Tetje C
authors.initials: TC
authors.lastname: van der Sluis
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Versluis
authors.affiliation: Plexxikon Inc., Berkeley, California, United States of America.
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D006801:Humans; D007167:Immunotherapy; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*
chemical_list: D016827:CD8 Antigens; D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor
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