RESUMO
Fluorescein-mediated sonodynamic therapy (FL-SDT) is an extremely promising approach for glioma treatment, resulting from the combination of low-intensity focused ultrasound (FUS) with a sonosensitizer. In the present study, we evaluated the efficacy and immunomodulation of SDT with fluorescein as the sonosensitizer in immunocompetent GL261 glioma mice for the first time. In vitro studies demonstrated that the exposure of GL261 cells to FL-SDT induced immunogenic cell death and relevant upregulation of MHC class I, CD80 and CD86 expression. In vivo studies were then performed to treat GL261 glioma-bearing mice with FL-SDT, fluorescein alone, or FUS alone. Perturbation of the glioma-associated macrophage subset within the immune microenvironment was induced by all the treatments. Notably, a relevant depletion of myeloid-derived suppressor cells (MDSCs) and concomitant robust infiltration of CD8+ T cells were observed in the SDT-FL-treated mice, resulting in a significant radiological delay in glioma progression and a consequent improvement in survival. Tumor control and improved survival were also observed in mice treated with FL alone (median survival 41.5 days, p > 0.0001 compared to untreated mice), reflecting considerable modulation of the immune microenvironment. Interestingly, a high circulating lymphocyte-to-monocyte ratio and a very low proportion of MDSCs were predictive of better survival in FL- and FL-SDT-treated mice than in untreated and FUS-treated mice, in which elevated monocyte and MDSC frequencies correlated with worse survival. The immunostimulatory potential of FL-SDT treatment and the profound modulation of most immunosuppressive components within the microenvironment encouraged the exploration of the combination of FL-SDT with immunotherapeutic strategies.
RESUMO
Intraoperative ultrasound (ioUS) is increasingly used in current neurosurgical practice. This is mainly explained by its affordability, handiness, multimodal real-time nature, and overall by its image spatial and temporal resolution. Identification of lesion and potential residue, analysis of the vascularization pattern, and characterization of the nature of the mass are only some of the advantages that ioUS offers to guide safe and efficient tumor resection. Technological advances in ioUS allow to achieve both structural and functional imaging. B-mode provides high-resolution visualization of the lesion and of its boundaries and relationships. Pioneering modes, such as contrast-enhanced ultrasound (CEUS), ultrasensitive Doppler, and elastosonography, are tools with great potential in characterizing different functional aspects of the lesion in a qualitative and quantitative manner. As already happening for many organs and pathologies, the combined use of different US modalities offers new insights in a multiparametric fashion. In this study, we present the potential of our multiparametric approach for ioUS during neuro-oncological surgery. In this effort, we provide a pictorial essay focusing on the most frequent pathologies: low- and high-grade gliomas, meningiomas, and brain metastases.
