title: GM-CSF promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-α.
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.
authors.affiliation: Authors' 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.
authors.forename: Gary
authors.initials: G
authors.lastname: Kohanbash
authors.forename: Kayla
authors.initials: K
authors.lastname: McKaveney
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Ueda
authors.forename: Arlan H
authors.initials: AH
authors.lastname: Mintz
authors.forename: Nduka
authors.initials: N
authors.lastname: Amankulor
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Fujita
authors.forename: John R
authors.initials: JR
authors.lastname: Ohlfest
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D000818:Animals; D017209:Apoptosis; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005910:Glioma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D001119:Arginase; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018793:Interleukin-13; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit
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