TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy

One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNF alpha. Subsequently, TNF alpha induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNF alpha blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNF alpha expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNF alpha expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNF alpha is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNF alpha as a concurrent therapy in GBMs.

Automated summary

The study revealed that GBM cells secrete IL-8 and CCL2 to stimulate GAMs to produce TNF alpha, which induces ECs activation. TNF alpha plays a crucial role in GBM therapy, as its high expression predicts a poor response to Bevacizumab.