Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Pires-Afonso Y

PROVIDER: S-EPMC9441003 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Pires-Afonso Yolanda Y Muller Arnaud A Grzyb Kamil K Oudin Anaïs A Yabo Yahaya A YA Sousa Carole C Scafidi Andrea A Poli Aurélie A Cosma Antonio A Halder Rashi R Coowar Djalil D Golebiewska Anna A Skupin Alexander A Niclou Simone P SP Michelucci Alessandro A

Molecular oncology 20220815 17

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 m ...[more]

PMID: 35838338

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Project description:Glioblastoma is the most common and uncompromising primary brain tumour and is characterized by a dismal prognosis despite aggressive treatment regimens. At the cellular level, these tumours are composed of a mixture of neoplastic cells and non-neoplastic cells, including tumour-associated macrophages and endothelial cells. Cerebral oedema is a near-universal occurrence in patients afflicted with glioblastoma and it is almost exclusively managed with the corticosteroid dexamethasone despite significant drawbacks associated with its use. Here, we demonstrate that dexamethasone blocks interleukin-1 production in both bone marrow-derived and brain resident macrophage populations following stimulation with lipopolysaccharide and interferon gamma. Additionally, dexamethasone is shown to inhibit downstream effectors of interleukin-1 signalling in both macrophage populations. Co-culture of bone marrow-derived macrophages with organotypic tumour slices results in an upregulation of interleukin-1 cytokines, an effect that is absent in co-cultured microglia. Genetic ablation of interleukin-1 ligands or receptor in mice bearing RCAS/tv-a-induced platelet-derived growth factor B-overexpressing glioblastoma results in reduced oedema and partial restoration of the integrity of the blood-brain barrier, respectively; similar to results obtained with vascular endothelial growth factor neutralization. We establish that tumours from dexamethasone-treated mice exhibit reduced infiltration of cells of the myeloid and lymphoid compartments, an effect that should be considered during clinical trials for immunotherapy in glioblastoma patients. Additionally, we emphasize that caution should be used when immune profiling and single-cell RNA sequencing data are interpreted from fresh glioblastoma patient samples, as nearly all patients receive dexamethasone after diagnosis. Collectively, this evidence suggests that interleukin-1 signalling inhibition and dexamethasone treatment share therapeutic efficacies and establishes interleukin-1 signalling as an attractive and specific therapeutic target for the management of glioblastoma-associated cerebral oedema.

Project description:Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin of the surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and programmed death-ligand 1 (an immune checkpoint) across human glioblastoma regions are understudied. In this study, we performed a quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers triggering receptor expressed on myeloid cells 2 and CD163, and the low-affinity-activating receptor CD32a), T cells, natural killer cells and programmed death-ligand 1, in 59 human IDH1-wild-type glioblastoma multi-regional samples (n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), programmed death-ligand 1 and CD4+ T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared with the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/triggering receptor expressed on myeloid cells 2 (anti-inflammatory) and CD8+ T cells in the invasive margins but not in the tumour core (P < 0.01). Programmed death-ligand 1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and triggering receptor expressed on myeloid cells 2, only in the leading edge of glioblastomas (P < 0.01). Similarly, there was a positive correlation between programmed death-ligand 1 expression and CD8+ T-cell infiltration in the leading edge (P < 0.001). There was no relationship between CD64 (a receptor for autoreactive T-cell responses) and CD8+/CD4+ T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335+) correlated with CD8+ T cells and with CD68/CD163/triggering receptor expressed on myeloid cells 2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (triggering receptor expressed on myeloid cells 2, CD163 and CD32a) and CD4+/CD8+/programmed death-ligand 1 RNA expression were validated (P < 0.001). Finally, multivariate analysis showed that high triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11, respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8+ T cells and programmed death-ligand 1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages, together with immune checkpoint inhibitors in cancer, these data have major clinical implications.

Dataset Information

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

Publications

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

Similar Datasets

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