[en] 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.
Disciplines :
Oncology
Author, co-author :
Pires-Afonso, Yolanda; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg ; Doctoral School of Science and Technology, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Muller, Arnaud; Quantitative Biology Unit, Bioinformatics Platform, Luxembourg Institute of Health, Luxembourg
Oudin, Anaïs; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg
Yabo, Yahaya A; Doctoral School of Science and Technology, University of Luxembourg, Esch-sur-Alzette, Luxembourg ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg
SOUSA, Carole ; University of Luxembourg ; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg
Scafidi, Andrea; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg ; Doctoral School of Science and Technology, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Poli, Aurélie; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg
COSMA, Antonio ; University of Luxembourg ; Quantitative Biology Unit, National Cytometry Platform, Luxembourg Institute of Health, Luxembourg
HALDER, Rashi ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Sequencing Platform
COOWAR, Djalil ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Rodent facility
GOLEBIEWSKA, Anna ; University of Luxembourg ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg
SKUPIN, Alexander ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Integrative Cell Signalling ; National Centre for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA, USA
NICLOU, Simone P. ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) ; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg ; KG Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Norway
MICHELUCCI, Alessandro ; University of Luxembourg ; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg
Action LIONS Vaincre le Cancer Fondation du Pélican de Mie et Pierre Hippert-Faber Fonds National de la Recherche Luxembourg Foundation for the National Institutes of Health H2020 Marie Skłodowska-Curie Actions
Funding text :
The authors thank Amandine Bernard for mouse genotyping and western blotting, Virginie Baus for helping with the MRI as well as Thomas Cerutti for the support with flow cytometry experiments. The authors are grateful to Dr Oihane Uriarte and Dr Tony Heurtaux for aiding with gentleMACS™ Dissociator. YPA and CS were supported by the Luxembourg National Research Fund (PRIDE15/10675146/CANBIO and AFR6916713, respectively) and the Fondation du Pélican de Mie et Pierre Hippert-Faber under the aegis of Fondation de Luxembourg. YAY was supported by GLIOTRAIN ITN funded by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 766069 (The material presented and views expressed here are the responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out). AS was supported by the C14/BM/7975668/CaSCAD project as well as by the National Biomedical Computation Resource (NBCR) through the NIH P41 GM103426 grant from the National Institutes of Health. AM was supported by Action Lions ‘Vaincre le Cancer’ Luxembourg. The authors acknowledge financial support by the Luxembourg Institute of Health (MIGLISYS) and the Luxembourg Centre for Systems Biomedicine.The authors thank Amandine Bernard for mouse genotyping and western blotting, Virginie Baus for helping with the MRI as well as Thomas Cerutti for the support with flow cytometry experiments. The authors are grateful to Dr Oihane Uriarte and Dr Tony Heurtaux for aiding with ™ Dissociator. YPA and CS were supported by the Luxembourg National Research Fund (PRIDE15/10675146/CANBIO and AFR6916713, respectively) and the Fondation du Pélican de Mie et Pierre Hippert‐Faber under the aegis of Fondation de Luxembourg. YAY was supported by GLIOTRAIN ITN funded by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 766069 (The material presented and views expressed here are the responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out). AS was supported by the C14/BM/7975668/CaSCAD project as well as by the National Biomedical Computation Resource (NBCR) through the NIH P41 GM103426 grant from the National Institutes of Health. AM was supported by Action Lions ‘Vaincre le Cancer’ Luxembourg. The authors acknowledge financial support by the Luxembourg Institute of Health (MIGLISYS) and the Luxembourg Centre for Systems Biomedicine. gentleMACS
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