Unraveling and targeting distinct immunosuppressive mechanisms in GBM

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Glioblastoma (GBM) is the most frequent and aggressive adult brain tumor, with 85% of patients dying within two years. Novel targeted therapies are urgently required, but despite efforts to subtype patients based on molecular and genetic profiles, available subtypes have yet failed to direct targeted treatment strategies. Immune checkpoint inhibitors (ICI) have created a paradigm shift in the treatment of several cancers due to their therapeutic efficacy in extending patient lives, but so far have failed in GBMs, due to their anergic and immunosuppressive characteristics. To this end, it remains unknown which pathways and signals in the GBM tumor microenvironment contribute to such therapy failure. Our laboratory has recently identified two immunosuppressive subtypes in ICI-non-responding IDHwt-GBM that are either immune-deserted and highly angiogenic (TIMElow) or immune-enriched with a more functional blood-brain barrier (TIMEhigh). I propose that different mechanisms cause the overall immunosuppression for which subtype-specific strategies need to be employed to evoke an immune response. Using genetically engineered GBM mouse tumor models and human GBM tissues, I will test my hypothesis by functionally characterizing the vascular immune environment in both TIME GBM subtypes and design specific and novel combinatorial immuno-oncology precision treatment strategies that increase T cell infiltration and activity in TIMElow GBM, and counteract the immunosuppressive immune cell functions in TIMEhigh GBM. Results forthcoming with partly repurposed and approved drugs will hopefully guide future trials in a timely manner to evoke an adequate immune response and prolong lifespan in GBM patients.