Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 3, Pages 997-1006Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1721434116
Keywords
anti-CD47; microglia; glioblastoma; immunotherapy; checkpoint inhibition
Categories
Funding
- NIH [NS069375]
- Swiss National Science Foundation [P-155336]
- Novartis Foundation for Medical-Biological Research
- Department of Neurosurgery, University Hospital Basel
- German Cancer Aid (Deutsche Krebshilfe)
- German Academic Scholarship Foundation
- Stanford Medical Scholars Translational Science Research Grant
- Price Family Charitable Fund
- Center for Children's Brain Tumors (Stanford University)
- Ty Louis Campbell Foundation St. Baldrick's Scholar
- Kathryn S.R. Lowry Endowed Chair
- American Brain Tumor Foundation
- Siebel Scholars Award from the Siebel Stem Cell Institute
- Emerson Collective Cancer Research Fund
- Pew Latin American Fellowship
- Virginia and D.K. Ludwig Fund for Cancer Research
- Tashia and John Morgridge Endowed Pediatric Faculty Scholar and Fellowships Awards
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Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRP alpha-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages (Ccr2(RFP)) and microglia (Cx3cr1(GFP)). We show that even in the absence of phagocytizing macrophages (Ccr2(RFP/RFP)), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications.
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