The vasculature as a target for therapy in brain tumors

Glioblastomas are aggressive gliomas with a grim prognosis, characterized extreme invasiveness and abnormal vessels.

The abnormal vessels can promote tumor progession by providing a route of invasion for glioma cells and by limiting T cell recruitment.

We have found that the C-type lectin CD93 is highly expressed in glioblastoma vessels and is important for organizing fibronectin in extracellular matrix. Our current data suggest that CD93 is necessary for migration of glioma cells along blood vessels.

The first aim of this proposal is to explore the mechanisms through which CD93 promotes perivascular migration, to find  therapeutic targets to block invasion. Here, we combine analysis of human glioblastomas with high quality in vitro and in vivo models of glioma invasion. The efficacy of cancer immunotherapy is hampered by an immunosuppressive microenvironment in glioblastoma.

Tumor vessels respond poorly to pro-inflammatory signals and express low levels of adhesion molecules and chemokines needed for T cell recruitment.

In the second aim of this proposal, we take a new approach to enhancing T cell recruitment, by transforming tumor vessels to a phenotype that resembles high endothelial venules (HEV) of lymphoid organs.

Therapeutic induction of HEV will be performed using an AAV-vector that target brain endothelal cells, and the effects will be investigated in experimental models of glioma. Our goal is to find new vascular targeting strategies to improve patient prognosis.