Yeo, Rawal, and Delcuze et al. performed a longitudinal analysis of the cellular composition of EGFR-driven GBM tumors throughout tumor progression at single-cell resolution. In humans and a mouse model, developing GBMs were enriched in proinflammatory microglia, whereas end-stage GBMs were enriched in anti-inflammatory macrophages and pro-tumorigenic MDSCs. An increase in anti-inflammatory macrophages and MDSCs paralleled the blood–brain barrier breakdown and extensive growth of tumor cells. Temozolomide treatment decreased MDSCs, and combination with irradiation led to increased intratumoral GzmB+CD8+ T cells and tumor control.
Contributed by Shishir Pant
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.