Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression

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.

Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

“…These polarized BMDMs showed an immunosuppression phenotype that significantly reduces the proliferation and IFNγ production of CD8 + T cells, posing a challenge to developing immunotherapy for GBM. A similar study was recently reported by Yeo et al (48), where the BMDM was observed with an increased proportion at the advanced stage of GBMs. Intriguingly, we found that knocking down ANXA1 significantly decreased the suppression effect of macrophages on CD8 + T cells, and tumor progression in GL261-derived syngeneic glioma mouse models, implying ANXA1 could be a potential target for GBM treatment.…”

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

“…This exploration of the TAM population also unveiled a shift from microglia-derived to monocyte-derived TAMs in the TME with tumor recurrence ( 203 ). Notably, high infiltration of monocytic macrophages relative to resident microglia corresponds to increased malignancy in gliomas ( 19 , 204 ). As for the tumor-infiltrating lymphoid population, TCR sequencing of newly diagnosed and recurrent GBMs revealed a diminished TCR repertoire with recurrence ( 22 ), which leads to suppressed T cell-mediated immune response via altered antigen-recognition machinery.…”

Immune surveillance in glioblastoma: Role of the NKG2D system and novel cell‐based therapeutic approaches

“…A recent study at the single‐cell level provided new insights into the dynamics of evolution of the immune landscape in the TME in in vivo model systems of GBM, which were confirmed in tumour samples from patients with low‐grade glioma and GBM, respectively. The results identified a large phenotypic heterogeneity at the early stage of GBM development 149 A drastic change in the innate immune cell composition during tumour progression was observed, with a preponderance of proinflammatory (M1‐like) microglia at the early stage followed by infiltration of protumorgenic MDSC (M2‐like) in late‐stage tumours 149 . These data highlight the importance of the immunosuppresive TME and its contribution to GBM immune escape and thus tumour progression.…”