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.
Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Sackler School of Graduate Studies, Tufts University School of Medicine,
Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Sackler School of Graduate Studies, Tufts University School of Medicine, Boston, MA, USA. (2) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. (3) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Sackler School of Graduate Studies, Tufts University School of Medicine, Boston, MA, USA. (4) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. (5) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. (6) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. (7) Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (8) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. (9) Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. (10) Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. (11) Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (12) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. vboussio@bidmc.harvard.edu. Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. vboussio@bidmc.harvard.edu. (13) Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. acharest@bidmc.harvard.edu. Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. acharest@bidmc.harvard.edu.
