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Cancer Res. 2013 Nov 1;73(21):6413-23. doi: 10.1158/0008-5472.CAN-12-4124. Epub 2013 Sep 12.

GM-CSF promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-α.

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  • 1Authors' Affiliations: Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health; Brain Tumor Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center; Departments of Neurological Surgery, Surgery, and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.

Abstract

Malignant gliomas are lethal cancers in the brain and heavily infiltrated by myeloid cells. Interleukin-4 receptor-α (IL-4Rα) mediates the immunosuppressive functions of myeloid cells, and polymorphisms in the IL-4Rα gene are associated with altered glioma risk and prognosis. In this study, we sought to evaluate a hypothesized causal role for IL-4Rα and myeloid suppressor cells in glioma development. In both mouse de novo gliomas and human glioblastoma cases, IL-4Rα was upregulated on glioma-infiltrating myeloid cells but not in the periphery or in normal brain. Mice genetically deficient for IL-4Rα exhibited a slower growth of glioma associated with reduced production in the glioma microenvironment of arginase, a marker of myeloid suppressor cells, which is critical for their T-cell inhibitory function. Supporting this result, investigations using bone marrow-derived myeloid cells showed that IL-4Rα mediates IL-13-induced production of arginase. Furthermore, glioma-derived myeloid cells suppressed T-cell proliferation in an IL-4Rα-dependent manner, consistent with their identification as myeloid-derived suppressor cells (MDSC). Granulocyte macrophage colony-stimulating factor (GM-CSF) plays a central role for the induction of IL-4Rα expression on myeloid cells, and we found that GM-CSF is upregulated in both human and mouse glioma microenvironments compared with normal brain or peripheral blood samples. Together, our findings establish a GM-CSF-induced mechanism of immunosuppression in the glioma microenvironment via upregulation of IL-4Rα on MDSCs.

PMID:
24030977
[PubMed - indexed for MEDLINE]
PMCID:
PMC3829000
[Available on 2014/11/1]
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