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Profiling of the immune landscape in murine glioblastoma following blood brain/tumor barrier disruption with MR image-guided focused ultrasound

Abstract

Purpose

Glioblastoma (GB) poses formidable challenges to systemic immunotherapy approaches owing to the paucity of immune infiltration and presence of the blood brain/tumor barriers (BBB/BTB). We hypothesize that BBB/BTB disruption (BBB/BTB-D) with focused ultrasound (FUS) and microbubbles (MB) increases immune infiltration in GB. As a prelude to rational combination of FUS with ITx, we herein investigate the impact of localized BBB/BTB-D on innate and adaptive immune responses in an orthotopic murine GB model.

Methods

Mice with GL261 gliomas received i.v. MB and underwent FUS BBB/BTB-D (1.1 MHz, 0.5 Hz pulse repetition frequency, 10 ms bursts, 0.4–0.6 MPa). Brains, meninges, and peripheral lymphoid organs were excised and examined by flow cytometry 1–2 weeks following FUS.

Results

The number of dendritic cells (DC) was significantly elevated in GL261 tumors and draining cervical LN in response to sonication. CD86 + DC frequency was also upregulated with 0.6 MPa FUS, suggesting increased maturity. While FUS did not significantly alter CD8 + T cell frequency across evaluated organs, these cells upregulated checkpoint molecules at 1 week post-FUS, suggesting increased activation. By 2 weeks post-FUS, we noted emergence of adaptive resistance mechanisms, including upregulation of TIGIT on CD4 + T cells and CD155 on non-immune tumor and stromal cells.

Conclusions

FUS BBB/BTB-D exerts mild, transient inflammatory effects in gliomas—suggesting that its combination with adjunct therapeutic strategies targeting adaptive resistance may improve outcomes. The potential for FUS-mediated BBB/BTB-D to modify immunological signatures is a timely and important consideration for ongoing clinical trials investigating this regimen in GB.

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Data availability

Data associated with this study are included in the main text or supplementary files for this article and are available from the corresponding author on reasonable request.

Code availability

N/A.

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Acknowledgements

The authors thank Dr. Sasha Klibanov (UVA) for supplying microbubbles for all FUS studies as well as Breanna Noffsinger (UVA) for her guidance and assistance with immunological characterization studies. Additional thanks to the UVA Carter Immunology Center for enabling generation of flow cytometry data.

Funding

This study was supported by National Institutes of Health Grants R01EB030409 and R21NS118278 (R.J.P.) and R01CA197111 (R.J.P. and T.N.J.B.), the Focused Ultrasound Foundation (T.N.J.B. and R.J.P.), the Melanoma Research Alliance (Grant #: 348727) and the Schiff Foundation (T.N.J.B. and R.J.P.). N.D.S. was supported by the National Institutes of Health Director’s Early Independence Award DP5 (DP5OD031846), National Cancer Institute F99/K00 Predoctoral to Postdoctoral Fellow Transition Award (F99CA234954 and K00CA234954), NSF Graduate Research Fellowship, and UVA School of Medicine Wagner Fellowship. A.R.W. was supported by an NIH Cancer Training Grant (2T32CA009109-41), the UVA Cancer Center Farrow Fellowship and NCI Cancer Center Support Grant P30 CA44579.

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Contributions

NDS and ARW designed and performed experiments and data analysis. NDS wrote the manuscript. WJG and GWM performed MR imaging and supported FUS studies. RJP and TNJB provided funding support, supervised all studies, and contributed to writing the manuscript. All authors reviewed and approved the manuscript.

Corresponding authors

Correspondence to Natasha D. Sheybani, Richard J. Price or Timothy N. J. Bullock.

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Mouse protocols were approved by the IACUC committee at the University of Virginia (UVA).

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Sheybani, N.D., Witter, A.R., Garrison, W.J. et al. Profiling of the immune landscape in murine glioblastoma following blood brain/tumor barrier disruption with MR image-guided focused ultrasound. J Neurooncol 156, 109–122 (2022). https://doi.org/10.1007/s11060-021-03887-4

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Keywords

  • Focused ultrasound
  • Image guidance
  • Glioblastoma
  • Blood brain barrier
  • Immune
  • Immunotherapy