Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression
Alan T. Yeo, Shruti Rawal, Bethany Delcuze, Anthos Christofides, Agata M. P. Atayde, Laura Strauss, Leonora Balaj, Vaughn A. Rogers, Erik J. Uhlmann, Hemant Varma, Bob S. Carter, Vassiliki A. Boussiotis, Al Charest
Abstract
Abstract Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM immune microenvironment during tumor evolution and standard of care treatments is limited. Using single-cell transcriptomics and flow cytometry, we unveiled large-scale comprehensive longitudinal changes in immune cell composition throughout tumor progression in an epidermal growth factor receptor-driven genetic mouse GBM model. We identified subsets of proinflammatory microglia in developing GBMs and anti-inflammatory macrophages and protumorigenic myeloid-derived suppressors cells in end-stage tumors, an evolution that parallels breakdown of the blood–brain barrier and extensive growth of epidermal growth factor receptor + GBM cells. A similar relationship was found between microglia and macrophages in patient biopsies of low-grade glioma and GBM. Temozolomide decreased the accumulation of myeloid-derived suppressor cells, whereas concomitant temozolomide irradiation increased intratumoral GranzymeB + CD8 + T cells but also increased CD4 + regulatory T cells. These results provide a comprehensive and unbiased immune cellular landscape and its evolutionary changes during GBM progression.