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Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

Noorani, I; Sidlauskas, K; Pellow, S; Savage, R; Norman, JL; Chatelet, DS; Fabian, M; ... Boche, D; + view all (2023) Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins. Brain Communications , 5 (3) , Article fcad176. 10.1093/braincomms/fcad176. Green open access

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Abstract

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.

Type: Article
Title: Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/braincomms/fcad176
Publisher version: https://doi.org/10.1093/braincomms/fcad176
Language: English
Additional information: © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
Keywords: glioblastoma, immunotherapy, intratumoural heterogeneity, macrophage, microglia
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10176277
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