Abstract
Background
The role of tumor-associated macrophages (TAMs) in glioblastoma (GBM) disease progression has received increasing attention. Recent advances have shown that TAMs can be re-programmed to exert a pro-inflammatory, anti-tumor effect to control GBMs. However, imaging methods capable of differentiating tumor progression from immunotherapy treatment effects have been lacking, making timely assessment of treatment response difficult. We showed that tracking monocytes using iron oxide nanoparticle (USPIO) with MRI can be a sensitive imaging method to detect therapy response directed at the innate immune system.
Methods
We implanted syngeneic mouse glioma stem cells into C57/BL6 mice and treated the animals with either niacin (a stimulator of innate immunity) or vehicle. Animals were imaged using an anatomical MRI sequence, R2* mapping, and quantitative susceptibility mapping (QSM) before and after USPIO injection.
Results
Compared to vehicles, niacin-treated animals showed significantly higher susceptibility and R2*, representing USPIO and monocyte infiltration into the tumor. We observed a significant reduction in tumor size in the niacin-treated group 7 days later. We validated our MRI results with flow cytometry and immunofluoresence, which showed that niacin decreased pro-inflammatory Ly6C high monocytes in the blood but increased CD16/32 pro-inflammatory macrophages within the tumor, consistent with migration of these pro-inflammatory innate immune cells from the blood to the tumor.
Conclusion
MRI with USPIO injection can detect therapeutic responses of innate immune stimulating agents before changes in tumor size have occurred, providing a potential complementary imaging technique to monitor cancer immunotherapies.
Manuscript highlight
We show that iron oxide nanoparticles (USPIOs) can be used to label innate immune cells and detect the trafficking of pro-inflammatory monocytes into the glioblastoma. This preceded changes in tumor size, making it a more sensitive imaging technique.
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Acknowledgements
This work is funded by an Alberta Innovates Health Solutions – Alberta Cancer Foundations Collaborative Research and Innovation Opportunities grant and by the Canadian Institutes of Health Research. KSR was supported by a Vanier Canada Graduate Scholarship, a Dr. T. Chen Fong Doctoral Scholarship, as well as a doctoral studentship from the Multiple Sclerosis Society of Canada.
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Appendix
Appendix
Diagram detailing the main MRI experiment. Three animals died (two in vehicle, one in niacin) prior to day 35 and thus could not be imaged on day 35.
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Yang, R., Hamilton, A.M., Sun, H. et al. Detecting monocyte trafficking in an animal model of glioblastoma using R2* and quantitative susceptibility mapping. Cancer Immunol Immunother 72, 733–742 (2023). https://doi.org/10.1007/s00262-022-03297-z
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DOI: https://doi.org/10.1007/s00262-022-03297-z