Funded Project 01

Glioblastoma remains one of the most aggressive and treatment-refractory cancers. Recent clinical trials investigating immune checkpoint inhibition have demonstrated highly heterogeneous responses, with most glioblastoma patients deriving no measurable benefit from immunotherapy. Our current work provides evidence that the epigenetic subclass of glioblastoma, as defined by methylation profiles (RTK1, RTK2, MES), could be a major determinant of immune cell composition and immune evasion strategies in the tumor microenvironment and thus might have a significant impact on the responsiveness of these tumors to checkpoint inhibition. We further hypothesize that these differences also translate to the systemic immune compartment and can be reflected in circulating immune cell markers.

This project aims to define the role of subclass-specific immune evasion strategies in glioblastomas, with the goal of identifying distinct mechanisms of immune evasion and vulnerabilities that may be exploited using immune checkpoint inhibitors or other therapeutic agents. To this end, we will analyze the tumor immune microenvironment in RTK1/2 and MES glioblastoma subtypes and evaluate how it adapts to neoadjuvant immunotherapy. We will further examine peripheral immune dysfunction and its correlation with the local intratumoral immune cell composition.

Our hypothesis is that RTK1/2 and MES tumors engage distinct immune evasion mechanisms that are both locally and systemically relevant and that this determines their differential response to immune checkpoint inhibition. A comprehensive analysis of intratumoral and peripheral immune responses in patients with glioblastoma will help to identify targetable pathways to overcome resistance and improve immunotherapeutic strategies.