IMMU-77. Defining steroid-induced immune barriers to immunotherapy in glioblastoma

Abstract Glucocorticoids like dexamethasone (dex) are widely used in glioblastoma to control cerebral edema, but emerging evidence suggests that dex induces durable immunosuppressive effects that can compromise immunotherapy efficacy. Our recent work shows that dex reprograms peripheral monocytes toward a stable immunosuppressive phenotype that persists through differentiation into tumor-associated myeloid cells (TAMs) and even after drug withdrawal, suggesting the induction of epigenetic memory. We hypothesize that systemic dex exposure in patients generates long-term immune suppression of the myeloid lineage by reprogramming bone marrow progenitors. To test this, we used ex vivo models and longitudinal patient samples. CD34⁺ hematopoietic stem cells were directed through defined progenitor stages into monocytes and co-cultured with glioblastoma organoids to generate TAMs. Dex was administered at discrete points during differentiation, and single-cell and epigenetic profiling were used to identify when immunosuppressive programming is established and how long it persists. In parallel, peripheral blood mononuclear cells are being collected from brain tumor patients before and after dex treatment. Myeloid phenotypes are being profiled and correlated with clinical dex exposure, including dose, timing, and duration. Finally, we assembled a high-resolution clinical dataset from 252 patients with high-grade glioma treated at University Hospitals Cleveland Medical Center, including detailed dex dosing trajectories, serial blood counts, surgical complications, survival data, and volumetric MRI scans. This dataset will help define how dex dose and duration relate to both symptom control and adverse events. These studies aim to determine how the magnitude and timing of dex exposure influence the persistence of immunosuppressive myeloid programming. By providing critical data on the durability and clinical impact of dex-induced immunosuppression, this work will guide decisions on steroid dosing, duration, and washout periods in future immunotherapy trials and support more informed steroid use in clinical neuro-oncology practice.