Endothelial cell‐derived angiopoietin‐2 is a therapeutic target in treatment‐naive and bevacizumab‐resistant glioblastoma

Abstract

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.

Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy

“…We observed an association of tumor vascular ANGPT2 expression and macrophage infiltration in patient tumors, suggesting that tumor vascular ANGPT2 may play a significant role in tumor macrophage recruitment. This is consistent with previous findings from animal studies that tumor-derived ANGPT2 and endothelial cell–specific overexpression of ANGPT2 promote tumor recruitment of macrophages(28,29,45,46). In addition, we showed that ANGPT2 promoted PD-L1 expression on M2-polarized macrophages.…”

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…Angiopoietin 2 (ANG2) is one potential biomarker of resistance to VEGF-targeted therapy. The results of some clinical studies using the VEGFA-neutralizing antibody bevacizumab have shown increased levels of circulating ANG2 after treatment 165 , whereas others have shown that serum ANG2 levels remain stable throughout the course of bevacizumab treatment 166 . In patients with ovarian cancer, however, a decrease in circulating ANG2 levels in response to VEGF pathway inhibition with sunitinib is correlated with a trend towards longer progression-free survival 167 .…”

“…ANG2 needs to be explored as a potential predictive and/or prognostic biomarker because high levels of ANG2 in the tumour or in the circulation are correlated with unfavourable patient survival across multiple cancer types, including glioblastoma 166 , neuroendocrine tumours 159 , ovarian cancer 160 , metastatic melanoma 161 , breast cancer 45 , hepatocellular carcinoma 168 , pancreatic ductal carcinoma 169 , and gastric carcinoma 170 (Supplementary Table S6). Moreover, high levels of circulating ANG2 are associated with unfavourable outcomes of bevacizumab-based therapy in colorectal carcinoma 171 .…”

The contribution of tumor-associated macrophages in glioma neo-angiogenesis and implications for anti-angiogenic strategies

“…The inhibition of Ang2 action together with the administration of bevacizumab or aflibercept results in significant improvement of therapeutic efficiency. 83 Recent studies showed that treatment with the Ang2/VEGF bispecific antibody shifted TAMs into an antitumor phenotype, consequently resulting in vascular normalization and tumor regression in a mouse glioblastoma model. 84,85 Following treatment with bevacizumab and cetuximab, the numbers of TAMs in glioblastoma and colorectal cancer increased and the cells became activated, respectively.…”