Effect of antiangiogenic therapy on tumor-associated macrophages in recurrent glioblastoma.

Abstract

2010 Background: Antiangiogenic therapy is associated with increased radiographic responses in glioblastoma (GBM), but tumors invariably recur. Tumor associated macrophages (TAMs) have been proposed as a mechanism of resistance to anti-angiogenic therapy in preclinical models. To examine the role of TAMs in recurrent GBM, we analyzed autopsy specimens from patients with or without history of antiangiogenic therapy. Methods: We compared autopsy brain specimens from 17 recurrent GBM patients who received anti-angiogenic treatment and chemoradiation (AAT+) to 7 patients who received chemotherapy and/or radiotherapy without anti-angiogenic therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically identified with flow cytometry and immunohistochemistry (IHC) with CD68, CD11b, CD14, and CD163 markers. All specimens were obtained from the Department of Pathology at Massachusetts General Hospital and clinical information gained through review of the patients’ records. Results: Using flow cytometry, we observed an increase in CD11b+CD14+ cells in the AAT+ patients compared to AAT- patients. Using IHC analysis, we observed a significant increase in CD68+ macrophages in the tumor bulk (p<0.01) and infiltrative areas (p<0.05) in AAT+ versus AAT- patients. We also observed a significant increase in CD11b+ myeloid cells in the tumor bulk (p<0.01) and a significant increase in CD163+ cells in the infiltrative areas (p<0.05) in the AAT+ group. Finally, we noted a trend toward an increase in CD163+ cells in the tumor bulk (p=0.087) in the AAT+ versus the AAT- patients. Conclusions: Patients with recurrent GBM after antiangiogenic therapy showed a significant increase in CD68+ TAMs and in CD11b+ cells in the tumor bulk. Additionally, antiangiogenic treatment induced an increase in CD68+ and CD163+ TAMs in the infiltrative region. These data indicate that TAMs may participate in escape from antiangiogenic therapy and may represent a future therapeutic target in recurrent GBM.