Search

Simple Summary: Glioblastoma is one of the most aggressive brain tumors, with poor survival and early recurrence rates. The development of effective immunotherapy treatments has been limited by the infiltration-resistant and immunosuppressive tumor microenvironments of these tumors. γδ T cells are unconventional T cells that have the potential to overcome these challenges through their unique recognition of molecular targets on glioblastoma cells. Nonetheless, challenges exist in the utilization of these cells, including their isolation, expansion, and potential for protumor activity. In this review, we discuss the biology of γδ T cells and their role in immunotherapy for glioblastoma and propose several research avenues for future studies. Cell-based immunotherapy for glioblastoma (GBM) encounters major challenges due to the infiltration-resistant and immunosuppressive tumor microenvironment (TME). γδ T cells, unconventional T cells expressing the characteristic γδ T cell receptor, have demonstrated promise in overcoming these challenges, suggesting great immunotherapeutic potential. This review presents the role of γδ T cells in GBM and proposes several research avenues for future studies. Using the PubMed, ScienceDirect, and JSTOR databases, we performed a review of the literature studying the biology of γδ T cells and their role in GBM treatment. We identified 15 studies focused on γδ T cells in human GBM. Infiltrative γδ T cells can incite antitumor immune responses in certain TMEs, though rapid tumor progression and TME hypoxia may impact the extent of tumor suppression. In the studies, available findings have shown both the potential for robust antitumor activity and the risk of protumor activity. While γδ T cells have potential as a therapeutic agent against GBM, the technical challenges of extracting, isolating, and expanding γδ T cells, and the activation of antitumoral versus protumoral cascades, remain barriers to their application. Overcoming these limitations may transform γδ T cells into a promising immunotherapy in GBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) is a common primary brain tumor with a short median overall survival despite aggressive treatment with resection, chemotherapy, and radiation therapy. Focused ultrasound (FUS) represents a promising new therapeutic approach for treatment of GBM. Unlike imaging forms of ultrasound, FUS can successfully penetrate the skull surrounding the brain, allowing for non-invasive ablation of tumor tissue. FUS can also temporarily disrupt the blood–brain barrier, a microvascular network that prohibits diffusion of most therapeutic agents, allowing chemotherapeutic drugs to penetrate the tumor. Other modalities are under investigation and include means of stimulating the immune system and sensitizing tumors to radiation therapy. The feasibility and safety of transcranial FUS has been illustrated in animal models and clinical trials. Precise results can be obtained under guidance from magnetic resonance imaging, limiting side effects. Successful outcomes from clinical trials will likely continue to motivate investigation and innovation of FUS technology for GBM. Glioblastoma (GBM) is an aggressive primary astrocytoma associated with short overall survival. Treatment for GBM primarily consists of maximal safe surgical resection, radiation therapy, and chemotherapy using temozolomide. Nonetheless, recurrence and tumor progression is the norm, driven by tumor stem cell activity and a high mutational burden. Focused ultrasound (FUS) has shown promising results in preclinical and clinical trials for treatment of GBM and has received regulatory approval for the treatment of other neoplasms. Here, we review the range of applications for FUS in the treatment of GBM, which depend on parameters, including frequency, power, pulse duration, and duty cycle. Low-intensity FUS can be used to transiently open the blood–brain barrier (BBB), which restricts diffusion of most macromolecules and therapeutic agents into the brain. Under guidance from magnetic resonance imaging, the BBB can be targeted in a precise location to permit diffusion of molecules only at the vicinity of the tumor, preventing side effects to healthy tissue. BBB opening can also be used to improve detection of cell-free tumor DNA with liquid biopsies, allowing non-invasive diagnosis and identification of molecular mutations. High-intensity FUS can cause tumor ablation via a hyperthermic effect. Additionally, FUS can stimulate immunological attack of tumor cells, can activate sonosensitizers to exert cytotoxic effects on tumor tissue, and can sensitize tumors to radiation therapy. Finally, another mechanism under investigation, known as histotripsy, produces tumor ablation via acoustic cavitation rather than thermal effects. [ABSTRACT FROM AUTHOR]