Open Access

Alexander Scholz, Patrick Nikolaus Harter, Sebastian Cremer, Burak H. Yalcin, Stefanie Gurnik, Maiko Yamaji, Mariangela Di Tacchio, Kathleen Sommer, Peter Baumgarten, Roy Oliver Bähr, Joachim Peter Steinbach, Jörg Trojan, Martin Glas, Ulrich Herrlinger, Dietmar Krex, Matthias Meinhardt, Astrid Weyerbrock, Marco Timmer, Roland Goldbrunner, Martina Deckert, Christian Braun, Jens Schittenhelm, Jochen Früh, Evelyn Ullrich, Michel Guy André Mittelbronn, Karl Plate, Yvonne Reiss

• Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.