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

in Nature immunology by Alan T Yeo, Shruti Rawal, Bethany Delcuze, Anthos Christofides, Agata Atayde, Laura Strauss, Leonora Balaj, Vaughn A Rogers, Erik J Uhlmann, Hemant Varma, Bob S Carter, Vassiliki A Boussiotis, Al Charest

TLDR

  • The study mapped the immune microenvironment of GBM during tumor evolution and treated with different therapies, revealing a complex dynamic between immune cells and the tumor.
  • Temozolomide and irradiation therapy had distinct effects on the immune microenvironment, with potential implications for cancer treatment.
  • Further research is needed to fully understand the immune landscape of GBM and develop effective immunotherapies.

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 receptorGBM 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 GranzymeBCD8T cells but also increased CD4regulatory T cells. These results provide a comprehensive and unbiased immune cellular landscape and its evolutionary changes during GBM progression.

Overview

  • The study investigated the immune microenvironment of glioblastoma (GBM) during tumor evolution and standard of care treatments using single-cell transcriptomics and flow cytometry.
  • The research focused on an epidermal growth factor receptor-driven genetic mouse GBM model and patient biopsies of low-grade glioma and GBM.
  • The primary objective was to identify comprehensive longitudinal changes in immune cell composition during tumor progression and to determine the effects of treatments on the immune microenvironment.

Comparative Analysis & Findings

  • The study identified subsets of proinflammatory microglia in developing GBMs and anti-inflammatory macrophages and protumorigenic myeloid-derived suppressor cells in end-stage tumors.
  • Temozolomide treatment decreased the accumulation of myeloid-derived suppressor cells, while concomitant temozolomide irradiation increased intratumoral GranzymeBCD8T cells but also increased CD4regulatory T cells.
  • Analyses of patient biopsies revealed a similar relationship between microglia and macrophages in low-grade glioma and GBM.

Implications and Future Directions

  • The study provides a comprehensive and unbiased immune cellular landscape of GBM progression, which can aid in the development of more effective treatments.
  • Future research directions include investigating the impact of different treatments on the immune microenvironment and identifying therapeutic targets for cancer immunotherapy.
  • Further studies are needed to confirm the findings in human GBM patient samples and to explore the potential of immunotherapy combinations for improved patient outcomes.
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