Molecular Identity Changes of Tumor-Associated Macrophages and Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Mouse Glioblastoma Model

Yanrong Zhang; Jing Wang; Sara Natasha Ghobadi; Haiyan Zhou; Ai Huang; Marco Gerosa; Qingyi Hou; Olivier Keunen; Anna Golebiewska; Frezghi G Habte; Gerald A Grant; Ramasamy Paulmurugan; Kevin S Lee; Max Wintermark

doi:10.1016/j.ultrasmedbio.2022.12.006

Molecular Identity Changes of Tumor-Associated Macrophages and Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Mouse Glioblastoma Model

Ultrasound Med Biol. 2023 May;49(5):1082-1090. doi: 10.1016/j.ultrasmedbio.2022.12.006. Epub 2023 Jan 28.

Authors

Affiliations

¹ Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA.
² Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA; Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
³ Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA; Acupuncture and Tuina School/Third Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
⁴ Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁵ Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA; Department of Diagnostic and Public Health, University of Verona, Verona, Italy.
⁶ Department of Radiology, Neuroradiology Division, Stanford University, Stanford, CA, USA; Department of Nuclear Medicine, Guangdong Provincial People's Hospital, Guangzhou, China.
⁷ In Vivo Imaging Facility, Luxembourg Institute of Health, Luxembourg.
⁸ Department of Oncology, Luxembourg Institute of Health, Luxembourg.
⁹ Department of Radiology, Molecular Imaging Program at Stanford, Stanford, CA, USA.
¹⁰ Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Molecular Imaging Program at Stanford (MIPS), Canary Center for Cancer Early Detection, Department of Radiology, Stanford University, Stanford, CA, USA.
¹² Departments of Neuroscience and Neurosurgery and Center for Brain, Immunology, and Glia, School of Medicine, University of Virginia, Charlottesville, VA, USA.
¹³ Department of Neuroradiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: Max.Wintermark@gmail.com.

Abstract

An orthotopically allografted mouse GL26 glioma model (Ccr2^RFP/wt-Cx3cr1^GFP/wt) was used to evaluate the effect of transient, focal opening of the blood-brain barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). BBB opening was induced by magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS) combined with microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors were quantified in microscopic images. Tumors in animals treated with a single session of MRgFUS did not exhibit significant changes in cell numbers when compared with tumors in animals not receiving FUS. However, tumors that received two or three sessions of MRgFUS had significantly increased amounts of both CX3CR1-GFP and CCR2-RFP cells. The effect of MRgFUS on immune cell composition was also characterized and quantified using flow cytometry. Glioma implantation resulted in increased amounts of lymphocytes, monocytes and neutrophils in the brain parenchyma. Tumors administered MRgFUS exhibited increased numbers of monocytes and monocyte-derived TAMs. In addition, MRgFUS-treated tumors exhibited more CD80+ cells in monocytes and microglia. In summary, transient, focal opening of the BBB using MRgFUS combined with microbubbles can activate the homing and differentiation of monocytes and induce a shift toward a more pro-inflammatory status of the immune environment in glioblastoma.

Keywords: Focused ultrasound; Glioblastoma; Magnetic resonance imaging–guided focused ultrasound; Microbubbles; Microglia and macrophage activation; Sterile inflammation; Tumor-associated macrophages and microglia.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Blood-Brain Barrier / diagnostic imaging
Disease Models, Animal
Glioblastoma* / diagnostic imaging
Glioblastoma* / pathology
Glioma*
Magnetic Resonance Imaging / methods
Mice
Microbubbles
Microglia / pathology
Tumor-Associated Macrophages / pathology

Abstract

Publication types

MeSH terms

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