Single-cell systems neuroimmunology reveals a highly immunosuppressive microenvironment in human glioblastomas contacting the ventricular stem cell niche

Abstract

Abstract Glioblastomas make up more than 60% of adult primary brain tumors and carry a 15 month overall survival despite aggressive standard-of-care therapy. Recent advances in immunotherapy offer an appealing alternative that may improve outcomes for patients with glioblastoma; however, clinical trials have proven unsuccessful due in part to a lack of predictive features that may inform responsiveness to immunotherapy. We have recently shown a strong correlation between 1) immune infiltration, 2) tumor cell phenotype, and 3) patient outcome. Further, patients whose tumors demonstrate radiographic contact with the ventricular-subventricular zone (V-SVZ) have reduced survival compared to patients whose tumors do not contact the V-SVZ. We therefore hypothesized that the V-SVZ acts as a previously unappreciated immunosuppressive microenvironment within the brain that promotes tumor growth by suppressing anti-tumor immunity. Primary human glioblastomas were disaggregated into single-cell suspensions and mass cytometry (CyTOF) measured >30 parameters in thirteen immune populations infiltrating human glioblastomas. Cutting-edge machine-learning tools identified key differences in the abundance and phenotypes of T cells, B cells, NK cells, microglia, and peripheral macrophages infiltrating ventricle-contacting gliomas. Further, enriched expression of immune checkpoint receptors (PD-1, TIGIT, LAG-3, TIM3) correlated with ventricular contact and outcome. These results provide key insights into the immune microenvironment of glioblastomas and elucidate several clinically actionable immunotherapeutic targets that may be used to optimize treatment strategies for glioblastoma patients based on V-SVZ contact status.