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Project C01

Vascular control of tumor immunity in the central nervous system

Gliomas are amongst the most malignant brain tumors across all ages. Standard treatments such as chemo- and radiotherapy are usually unable to prevent tumor progression. While immunotherapies improve prognosis in systemic tumors such as skin and lung cancer, their effectiveness within the central nervous system (CNS) is limited. A reason for the lack of efficacy in brain tumors is their structurally and functionally aberrant vasculature limiting access and function of tumor-fighting immune cells. This project aims to identify and therapeutically modulate angiocrine mediators within the brain tumor vasculature to improve anti-tumor immunity. 
In the first funding period we tested the functional relevance of endothelial biomarkers of immune response for regulating angiocrine inflammation. We characterized the immune-vascular microenvironment and identified novel angiocrine mediators both in brain tumor models and human tissue. We delineated how radiotherapy induces neuroinflammation in patients with multiple sclerosis and angiocrine inflammation in gliomas. Further, we established the role of activated tumor vasculature recruiting CXCR3+ tumor-specific T cells. These findings led to the identification of distinct inflammatory endothelial subsets in human glioblastoma. In the current project, we will validate the role of the candidate gene A20/TNFAIP3 for angiocrine neuro-inflammation in murine models and human tissue. Based on an integration of single-cell and spatial sequencing data, we will decipher the impact of vascular heterogeneity on CNS tumor immunity in both primary brain tumors and brain metastasis. The intra-tumoral analysis will be complemented by inter-patient analysis as well as mouse models of ageing to investigate how age affects anti-tumor immunity. We expect the results to translate into novel vasculature-targeting treatment strategies to enhance antitumor immunity and thus improve the prognosis of patients with malignant brain tumors.

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