title: Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma.
abstract: In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we used genetically engineered and GL261-induced mouse models in combination with CX3CR1GFP/WT;CCR2RFP/WTdouble knock-in mice. Using this approach, we demonstrated that CX3CR1LoCCR2Himonocytes were recruited to the GBM, where they transitioned to CX3CR1HiCCR2Lomacrophages and CX3CR1HiCCR2-microglia-like cells. Infiltrating macrophages/monocytes constituted approximately 85% of the total TAM population, with resident microglia accounting for the approximately 15% remaining. Bone marrow-derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via geneticCcl2reduction prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm.Cancer Res; 77(9); 2266-78. ©2017 AACR.
authors.affiliation: Department of Pediatrics and Aflac Cancer Center of Children's Health Care of Atlanta, Emory University School of Medicine, Atlanta, Georgia.|Department of Neurosciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Neurosciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Xi
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Pediatrics and Aflac Cancer Center of Children's Health Care of Atlanta, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Herting
authors.affiliation: Department of Neurosciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Virginia Alvarez
authors.initials: VA
authors.lastname: Garcia
authors.affiliation: Department of Pediatrics and Aflac Cancer Center of Children's Health Care of Atlanta, Emory University School of Medicine, Atlanta, Georgia.|Department of Neurosciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Kai
authors.initials: K
authors.lastname: Nie
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Winnie W
authors.initials: WW
authors.lastname: Pong
authors.affiliation: Department of Neurosciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
authors.forename: Rikke
authors.initials: R
authors.lastname: Rasmussen
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Bhakti
authors.initials: B
authors.lastname: Dwivedi
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Seby
authors.affiliation: Department of Cellular Neuroscience, Max-Delbrück-Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Wolf
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.affiliation: Department of Pediatrics and Aflac Cancer Center of Children's Health Care of Atlanta, Emory University School of Medicine, Atlanta, Georgia. dhambar@emory.edu.
authors.forename: Dolores
authors.initials: D
authors.lastname: Hambardzumyan
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D009000:Monocytes / Q000473:pathology; D054390:Receptors, CCR2 / Q000096:biosynthesis / Q000235:genetics*; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515335:Ccr2 protein, mouse; C471885:Cx3cr1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine