4.7 Article

Elucidating tumour-associated microglia/macrophage diversity along glioblastoma progression and under ACOD1 deficiency

期刊

MOLECULAR ONCOLOGY
卷 16, 期 17, 页码 3167-3191

出版社

WILEY
DOI: 10.1002/1878-0261.13287

关键词

ACOD1; IRG1; glioblastoma; heterogeneity; metabolic reprogramming; single-cell RNA-sequencing; tumour-associated microglia; macrophages

类别

资金

  1. Luxembourg National Research Fund [PRIDE15/10675146/CANBIO, AFR6916713]
  2. Fondation du Pelican de Mie et Pierre Hippert-Faber under the aegis of Fondation de Luxembourg
  3. European Union's Horizon 2020 research and innovation programme under the Marie Skodowska-Curie [766069]
  4. C14/BM/7975668/CaSCAD
  5. National Biomedical Computation Resource (NBCR) through the NIH from the National Institutes of Health [P41 GM103426]
  6. Action Lions 'Vaincre le Cancer' Luxembourg
  7. Luxembourg Institute of Health (MIGLISYS)
  8. Luxembourg Centre for Systems Biomedicine

向作者/读者索取更多资源

This study comprehensively investigates the cellular and molecular changes of tumour-associated microglia/macrophages (TAMs) in glioblastoma and reveals the heterogeneity of TAMs and their metabolic adaptation along tumour progression. The findings provide insights into TAM heterogeneity and highlight the role of Acod1 in TAM adaptation during glioblastoma progression.
In glioblastoma (GBM), tumour-associated microglia/macrophages (TAMs) represent the major cell type of the stromal compartment and contribute to tumour immune escape mechanisms. Thus, targeting TAMs is emerging as a promising strategy for immunotherapy. However, TAM heterogeneity and metabolic adaptation along GBM progression represent critical features for the design of effective TAM-targeted therapies. Here, we comprehensively study the cellular and molecular changes of TAMs in the GL261 GBM mouse model, combining single-cell RNA-sequencing with flow cytometry and immunohistological analyses along GBM progression and in the absence of Acod1 (also known as Irg1), a key gene involved in the metabolic reprogramming of macrophages towards an anti-inflammatory phenotype. Similarly to patients, we identify distinct TAM profiles, mainly based on their ontogeny, that reiterate the idea that microglia- and macrophage-like cells show key transcriptional differences and dynamically adapt along GBM stages. Notably, we uncover decreased antigen-presenting cell features and immune reactivity in TAMs along tumour progression that are instead enhanced in Acod1-deficient mice. Overall, our results provide insight into TAM heterogeneity and highlight a novel role for Acod1 in TAM adaptation during GBM progression.

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