Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma.

Hutter, Gregor

Theruvath, Johanna

Graef, Claus Moritz

Zhang, Michael

Schoen, Matthew Kenneth

Manz, Eva Maria

Bennett, Mariko L

Olson, Andrew

Azad, Tej D

Sinha, Rahul

Chan, Carmel

Assad Kahn, Suzana

Gholamin, Sharareh

Wilson, Christy

Grant, Gerald

He, Joy

Weissman, Irving L

Mitra, Siddhartha S

Cheshier, Samuel H

2022-09-30T17:54:24Z

2022-09-30T17:54:24Z

2019-01

2022-09-30T17:54:22Z

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 SIRPα-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.

1721434116

0027-8424

1091-6490

https://hdl.handle.net/10161/25896

eng

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences of the United States of America

10.1073/pnas.1721434116

Microglia

Monocytes

Macrophages

Animals

Mice, Inbred NOD

Mice, Transgenic

Mice

Glioblastoma

Brain Neoplasms

Neoplasms, Experimental

Receptors, Immunologic

Neoplasm Proteins

Signal Transduction

Phagocytosis

CD47 Antigen

Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma.

Journal article

Grant, Gerald|0000-0002-2651-4603

997

1006

3

Duke

School of Medicine

Clinical Science Departments

Institutes and Centers

Duke Cancer Institute

Neurosurgery

Published

116