Immune cell identity behind the Ktrans mapping of mouse glioblastoma

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

doi:10.1016/j.mri.2023.06.008

Immune cell identity behind the K^trans mapping of mouse glioblastoma

Magn Reson Imaging. 2023 Nov:103:92-101. doi: 10.1016/j.mri.2023.06.008. Epub 2023 Jun 21.

Authors

Yanrong Zhang¹, Olivier Keunen², Anna Golebiewska³, Marco Gerosa⁴, Jing Wang⁵, Sara Natasha Ghobadi⁶, Ai Huang⁷, Qingyi Hou⁸, Frezghi G Habte⁹, Ningrui Li¹⁰, Gerry Grant¹¹, Ramasamy Paulmurugan¹², Kevin S Lee¹³, Max Wintermark¹⁴

Affiliations

¹ Department of Radiology, Neuroradiology Division, Stanford University, CA, USA; Stanford Shared FACS Facility, Stanford University, CA, USA.
² Department of Radiology, Neuroradiology Division, Stanford University, CA, USA; In Vivo Imaging Facility, Quantitative Biology Unit, Luxembourg Institute of Health Transversal Activities, 84 Val Fleuri, L-1526, Luxembourg.
³ Department of Radiology, Neuroradiology Division, Stanford University, CA, USA; Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, L-1526, Luxembourg.
⁴ Department of Radiology, Neuroradiology Division, Stanford University, CA, USA; Department of Diagnostic and Public Health, University of Verona, Verona 37135, Italy.
⁵ Department of Radiology, Neuroradiology Division, Stanford University, CA, USA; Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jing-wu Road, Jinan 250021, China.
⁶ Department of Radiology, Neuroradiology Division, Stanford University, CA, USA.
⁷ Department of Radiology, Neuroradiology Division, Stanford University, CA, USA; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
⁸ Department of Radiology, Neuroradiology Division, Stanford University, CA, USA; Nuclear Medicine Department, Guangdong Provincial People's Hospital, Guangzhou 510080, China.
⁹ Stanford Center for Innovation in In vivo Imaging (SCi3), Stanford University, CA, USA.
¹⁰ Department of Radiology, Stanford University, Stanford, CA, USA.
¹¹ Department of Neurosurgery, Stanford University School of Medicine, CA 94305, USA.
¹² Molecular Imaging Program at Stanford (MIPS), Canary Center for Cancer Early Detection, Department of Radiology, Stanford University, CA, USA.
¹³ Departments of Neuroscience and Neurosurgery and Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia, USA. Electronic address: ksl3h@virginia.edu.
¹⁴ Department of Neuroradiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: max.wintermark@gmail.com.

PMID: 37353182
PMCID: PMC10528281 (available on 2024-11-01)
DOI: 10.1016/j.mri.2023.06.008

Abstract

Dynamic contrast-enhanced MR imaging (DCE-MRI) can assess the integrity of the blood brain barrier (BBB) and has been used in GBM patients to determine glioma grade, predict prognosis, evaluate treatment response, and differentiate treatment-induced effect from recurrence. The volume transfer constant K^trans is the most frequently used metric in tumor assessment. Based on previous studies that a higher WHO grade of brain tumor was associated with greater impairments of immunity and that K^trans value was associated with the pathological grading, the relationship between differential composition of immune cells in GBM tissue and dynamic changes in K^trans mapping was anticipated in this study. The present study utilized an orthotopic allograft model of GBM in which mouse GL26 cells are implanted into Ccr2^RFP/wtCx3cr1^GFP/wt mice on a C57 background. The brain tumors exhibited heterogenous K^trans values with the coefficients of variation (CV) above 75%, or relatively homogeneous K^trans maps with CV values below 50%. The K^trans values of homogeneous tumors ranged between 0.02/min-0.32/min with a median value of 0.10/min. The immune cell composition defined by quantitative immunohistochemistry and cell sorting was compared between the tumors with K^trans values above 0.10/min (higher K^trans) or below 0.10/min (lower K^trans). Histological analysis showed that tumors with higher K^trans values exhibited greater numbers of CCR2^pos cells (257.60 ± 16.42/mm² vs 203.23 ± 12.20/mm², p = 0.04) and an increased ratio of CCR2^pos cells to CX3CR1^pos cells (1.20 ± 0.02 vs 0.38 ± 0.04, p = 0.001), the numbers of CX3CR1^pos cells did not differ significantly based on K^trans values (219.70 ± 16.20/mm² vs 250.38 ± 21.20/mm², p = 0.19). Flowcytometry analysis showed that tumors with higher K^trans values (above 0.1/min) were associated with greater numbers of both overall monocytes (54.93 ± 6.81% vs 29.75 ± 3.54%, p = 0.01) and inflammatory monocytes (72.38 ± 1.49% vs 59.52 ± 2.44%, p = 0.001). In contrast, tumors with lower K^trans values (below 0.1/min) exhibited greater numbers of patrolling monocytes (75.65 ± 4.14% vs 63 ± 6.94%, p = 0.05). In the tumors with lower K^trans values, all three types of tumor associated cells, including patrolling monocytes, inflammatory monocytes, and microglia cells possessed a higher proportion of cells at pro-inflammatory status (41.77 ± 6.13% vs 25.06 ± 6.72%, p = 0.05; 27.50 ± 2.11% vs 20.62 ± 1.87%, p = 0.03; and 55.80 ± 9.88% vs 31.12 ± 7.31%, p = 0.05), inflammatory monocytes showed fewer anti-inflammatory cells (1.25 ± 0.62% vs 3.16 ± 3.56%, p = 0.04). Taken together, differences in K^trans values were associated with differential immune cell phenotypes and polarizations. K^trans mapping may therefore represent a novel approach for defining the immune status of GBM.

Keywords: DCE-MRI; Glioblastoma; Immune cell identity; K(trans); TAMs.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain Neoplasms* / diagnostic imaging
Brain Neoplasms* / pathology
Contrast Media
Glioblastoma* / pathology
Glioma* / pathology
Magnetic Resonance Imaging / methods
Mice

Substances

Contrast Media

Abstract

Publication types

MeSH terms

Substances

Grants and funding