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

Marjolein Sluijter; Tetje C van der Sluis; Pieter A van der Velden; Mieke Versluis; Brian L West; Sjoerd H van der Burg; Thorbald van Hall

doi:10.1371/journal.pone.0104230

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

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

Authors

Marjolein Sluijter¹, Tetje C van der Sluis², Pieter A van der Velden³, Mieke Versluis³, Brian L West⁴, Sjoerd H van der Burg¹, Thorbald van Hall¹

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8 Antigens / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Combined Modality Therapy
Humans
Immunotherapy*
Macrophages / drug effects
Macrophages / immunology
Male
Melanoma, Experimental / enzymology
Melanoma, Experimental / immunology
Melanoma, Experimental / pathology
Melanoma, Experimental / therapy*
Mice
Protein Kinase Inhibitors / pharmacology*
Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
T-Lymphocytes / drug effects*
T-Lymphocytes / immunology*

Substances

CD8 Antigens
Protein Kinase Inhibitors
Receptor, Macrophage Colony-Stimulating Factor

Grants and funding

This work was supported by the department of Clinical Oncology and the Dutch Cancer Society (www.kwf.nl; grant UL2009-4400, SvdB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Co-author Brian L. West is employed by a commercial company Plexxikon Inc. Plexxikon Inc. provided support in the form of salary, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section.