title: CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells.
abstract: In many aggressive cancers, such as glioblastoma multiforme, progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). However, the mechanistic details of how Tregs and MDSCs are recruited in various tumors are not yet well understood. Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+Treg and CCR2+Ly-6C+monocytic MDSCs in this disease setting. In murine gliomas, we established novel roles for tumor-derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia. Tumors grown in CCL2-deficient mice failed to maximally accrue Tregs and monocytic MDSCs. In mixed-bone marrow chimera assays, we found that CCR4-deficient Treg and CCR2-deficient monocytic MDSCs were defective in glioma accumulation. Furthermore, administration of a small-molecule antagonist of CCR4 improved median survival in the model. In clinical specimens of glioblastoma multiforme, elevated levels of CCL2 expression correlated with reduced overall survival of patients. Finally, we found that CD163-positive infiltrating macrophages were a major source of CCL2 in glioblastoma multiforme patients. Collectively, our findings show how glioma cells influence the tumor microenvironment to recruit potent effectors of immunosuppression that drive progression. Cancer Res; 76(19); 5671-82. ©2016 AACR.
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Committee on Cancer Biology, The University of Chicago, Chicago, Illinois.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Chang
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Jason
authors.initials: J
authors.lastname: Miska
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Wainwright
authors.affiliation: Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana. Section of Neurosurgery, Department of Surgery, The University of Chicago Hospitals, Chicago, Illinois.
authors.forename: Mahua
authors.initials: M
authors.lastname: Dey
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Claudia V
authors.initials: CV
authors.lastname: Rivetta
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Dou
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kanojia
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Katarzyna C
authors.initials: KC
authors.lastname: Pituch
authors.affiliation: Section of Neurosurgery, Department of Surgery, The University of Chicago Hospitals, Chicago, Illinois. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jian
authors.initials: J
authors.lastname: Qiao
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Meijing
authors.initials: M
authors.lastname: Wu
authors.affiliation: Section of Neurosurgery, Department of Surgery, The University of Chicago Hospitals, Chicago, Illinois.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Horbinski
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Atique U
authors.initials: AU
authors.lastname: Ahmed
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. maciej.lesniak@northwestern.edu.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000401:mortality; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000502:physiology*; D005910:Glioma / Q000276:immunology* / Q000401:mortality; D006801:Humans; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology*; D054398:Receptors, CCR4 / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D059016:Tumor Microenvironment
chemical_list: C111835:CCL2 protein, human; C515354:CCR4 protein, human; D018932:Chemokine CCL2; D054398:Receptors, CCR4