Spatial single-cell profiling of deeply matched extreme long-term surviving glioblastoma patients reveals a distinct immune and stem cell driven ecosystem

Inter- and intratumoral heterogeneity have been suggested to substantially contribute to variations in tumoral behavior and survival in Glioblastoma (GBM). However, the exact contribution of the interplay between cancer cells and their microenvironment remains poorly understood. From a cohort of 2632 GBM patients, we selected 12 extreme long-term GBM survivors (eLTS, survival over 10 years) and 22 rigorously clinically matched short-term survivors (STS, survival less than 20 months). We compared the spatial composition and cellular interactions within the tumor microenvironment using high-dimensional, multiplexed immunofluorescence and spatial transcriptomics. Through extensive data analysis, we identified a specific perivascular niche in STS patients marked by a strong enrichment of the immunosuppressive milieu featuring CD133+ Glioma Stem Cells (GSCs), alternatively activated HMOX1 ^high /PDL1 ^high macrophages (MFs), and exhausted T-cytotoxic lymphocytes (Tcyts). By contrast, eLTS patients were characterized by an enrichment of immunocompetent HLA-DR ^high MFs and Tcyts that infiltrate deep into the tissue. Our work offers insights into the unique stem cells and immunosuppressive-driven ecosystems that underlie substantial differences in survival in GBM patients.