Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas (GBMs), but tumors invariably recur. Because tumor-associated macrophages (TAMs) have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of TAMs in recurrent glioblastoma (rGBM) patients. We compared autopsy brain specimens from 20 rGBM patients who received antiangiogenic treatment and chemoradiation (AAT+) to 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry (IHC) for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in TAMs in the AAT+ patients. IHC analysis demonstrated an increase in CD68+ TAMs in the tumor bulk (p<0.01) and infiltrative areas (p=0.02) in AAT+ patients. We also observed an increase in CD11b+ cells in the tumor bulk (p<0.01) and an increase in CD163+ TAMs in infiltrative tumor (p=0.02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumor (p=0.05 and p=0.05, respectively) correlated with poor overall survival in patients who first received antiangiogenic therapy at recurrence. In summary, rGBMs 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 in rGBM patients. These data suggest that TAMs may participate in escape from antiangiogenic therapy and may represent a potential biomarker of resistance and a potential therapeutic target in rGBM.

Citation Format: Christine Lu-Emerson, Matija Snuderl, Nathaniel D. Kirkpatrick, Jermaine Goveia, Jennie Taylor, Christian Davidson, Yuhui Huang, Lars Riedemann, S. Percy Ivy, G. Dan Duda, Marek Ancukiewicz3, Scott R. Plotkin, Andrew Chi, Elizabeth R. Gerstner, April F. Eichler, Jorg Dietrich, Anat O. Stemmer-Rachamimov, Tracy T. Batchelor, Rakesh K. Jain. Increase in tumor-associated macrophages (TAMs) after antiangiogenic therapy is associated with poor survival in recurrent glioblastoma (GBM) patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-339. doi:10.1158/1538-7445.AM2013-LB-339