LAUSR

Introduction Glioblastoma (GBM) is a malignant brain tumor characterized by diffuse brain invasion, molecular and cellular heterogeneity, and immune evasion, making current chemo-radiation treatments and emerging immunotherapies minimally effective. Transcranial MRI-guided focused ultrasound (MRgFUS) is a novel therapeutic modality, enabling the safe and targeted application of ultrasound energy in the brain. Recently, we demonstrated how MRgFUS can be used to transiently disrupt the blood-brain barrier (BBB) for enhanced delivery of stem cells and locally administered nanoparticles. In addition to creating structural effects, MRgFUS exposures are also capable of generating effects at the molecular level by modulating the levels of cytokines, chemokines and trophic factors in a tempo-spatially controlled manner. In the current study, we investigated the effects of MRgFUS on the GBM immune microenvironment. Materials and Methods C57BL/6 mice were implanted with luciferase expressing mouse GL261 glioma cells in the right striatum. MRgFUS exposures were applied using an MRI-guided system. Tumor, spleen, and superficial lymph nodes were collected seven days after MRgFUS treatment. Flow cytometry and immunohistochemistry were performed for the following antibodies: CD45-PE, CD3-FITC, CD8-PErCp/Cy5.5, TIM3-BV605, PD-1-PacBlue, CD4-APC, Nk1.1-FITC, Cd11b-Percp/Cy5.5, CD11c-B650, CD86-APC, GR1-PacBlue, FoxP3-PE, and CD25-APC. Statistical analysis of the data was performed using unpaired T-tests. Results MRgFUS treatment of tumors resulted in a statistically significant increase in the percentage of Foxp3+ CD25+ T-regulatory cells (Tregs) in the spleen compared to untreated controls. Analysis of superficial cervical lymph nodes following MRgFUS treatment revealed that myeloid-derived suppressor cells (MDSCs) were significantly increased while CD8+ T cells were significantly decreased in MRgFUS-treated tumors compared to untreated controls. Conclusions These findings suggest that MRgFUS treatment of intracranial GBM tumors results in the redistribution of key immune cell types within the tumor microenvironment as well as the body lymphoid tissues. Specifically, we found that Tregs and MDSCs moved away from the tumor, and CD8+ T cells moved into the tumor at 1 week post-treatment. This suggests that MRgFUS has the potential to awaken the suppressed GBM microenvironment and augment immunotherapy in brain cancer. Additional studies to help elucidate the underlying mechanisms and further evaluate the potential of this approach are ongoing. Citation Format: Pavlos Anastasiadis, Kenisha Younger, Nathan B. Roberts, Joseph A. Frank, Victor Frenkel, Eduardo Davila, Graeme Woodworth. Acoustic activation of the glioma-brain microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2103.