title: Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma.
abstract: Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas, but tumors invariably recur. Because tumor-associated macrophages have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of macrophages in patients with recurrent glioblastoma. We compared autopsy brain specimens from 20 patients with recurrent glioblastoma who received antiangiogenic treatment and chemoradiation with 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy or no treatment. Tumor-associated macrophages were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in macrophages in the antiangiogenic-treated patients. Immunohistochemical analysis demonstrated an increase in CD68+ macrophages in the tumor bulk (P < .01) and infiltrative areas (P = .02) in antiangiogenic-treated patients. We also observed an increase in CD11b+ cells in the tumor bulk (P < .01) and an increase in CD163+ macrophages in infiltrative tumor (P = .02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumors (P = .05 and P = .05, respectively) correlated with poor overall survival among patients who first received antiangiogenic therapy at recurrence. In summary, recurrent glioblastomas showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after antiangiogenic therapy. Higher numbers of CD11b+ cells correlated with poor survival among these patients. These data suggest that tumor-associated macrophages may participate in escape from antiangiogenic therapy and may represent a potential biomarker of resistance and a potential therapeutic target in recurrent glioblastoma.
authors.affiliation: Department of Neurology, Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Lu-Emerson
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Kirkpatrick
authors.forename: Jermaine
authors.initials: J
authors.lastname: Goveia
authors.forename: Christian
authors.initials: C
authors.lastname: Davidson
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.forename: Lars
authors.initials: L
authors.lastname: Riedemann
authors.forename: Jennie
authors.initials: J
authors.lastname: Taylor
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Scott R
authors.initials: SR
authors.lastname: Plotkin
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
authors.forename: April F
authors.initials: AF
authors.lastname: Eichler
authors.forename: Jorg
authors.initials: J
authors.lastname: Dietrich
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer-Rachamimov
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D015703:Antigens, CD / Q000378:metabolism; D001344:Autopsy; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D059016:Tumor Microenvironment / Q000187:drug effects*; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D014408:Biomarkers, Tumor
keywords: antiangiogenic therapy; glioblastoma; myeloid cells; relapse