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.

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

Grant support

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.